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G -Coupled Receptors Product Listing | Edition 1

Opium Poppy A source of

GPCR Products by Class • Class A: -like • Class B: -like • Class C: Glutamate • Class F: • GPCR Signaling Tocris Product Listing Series Contents This listing contains over 450 products, including , antagonists and allosteric modulators for a wide range of -coupled receptors (GPCRs). GPCRs are divided into their respective classes: Rhodopsin-like (class A), Secretin-like (class B), Glutamate (class C) and Frizzled (class F). Products for GPCR signaling are also listed.

Class A: Rhodopsin-like 4 Class A9 10 Class B: Secretin-like 22 Receptors Class A1/A2 4 and Related Receptors Y Receptors CC Chemokine Receptors Corticotropin-releasing Factor Tachykinin Receptors CXC Chemokine Receptors Receptors Class A11 11 GIP GPCR Crystal Structures 5 Free Fatty Acid Receptors Receptor Class A2 6 Hydroxycarboxylic Acid Receptors Glucagon-Like Receptors

Estrogen (GPER) Receptors Class A11/12 11 PACAP Receptor

Class A3 6 Purinergic Receptors Parathyroid Receptors

Angiotensin Receptors Class A12 12 Receptors Platelet-activating Factor Receptor VIP Receptors Receptors Class A13 12 Class C: Glutamate 24 Class A4 6 Receptors -sensing Receptor Receptors Receptors GABA Receptors Neuropeptide W/B Receptors B Sphingosine-1-phosphate Receptors Glutamate (Metabotropic) Receptors Receptors Class A13/15 13 GPCR Allostery 27 Class A5 7 Receptors Receptors Class A14 14 Class F: Frizzled 28 Receptors Prostanoid Receptors Receptor Leukotriene Receptors Thromboxane (TP) Receptors Melanin-concentrating Hormone GPCR Signaling 29 Class A15 14 (MCH) Receptors GPR35 Urotensin-II Receptors Protease-activated Receptors cAMP Class A6 8 G Protein (Heterotrimeric) Class A17 15 Receptors GRK Receptors GnRH Receptor IP Receptor Receptors 3 GPR103 Phospholipases 1 Receptor Receptors Receptor Class A17/18 17 Bias Signaling 30 Receptors Receptors References and Further Reading 31 Class A17/19 18 Class A7 9 Receptors 5-HT Receptors Receptors Class A18 19 Receptor Adenosine Receptors Receptor Acetylcholine Muscarinic Receptors

Neuromedin U Receptors Other GPCRs 21 Receptors Neuropeptide FF/AF Receptors Thyrotropin-Releasing Hormone Orphan GPCRs Receptors Sensory -specific Receptors

Class A8 10 DREADD Ligands 21 Formyl Peptide Receptors

2 | GPCR research Introduction GPCRs are transmembrane receptors that mediate from the cytosol to the cell interior. There are approximately 850 known GPCRs, which make up the largest receptor superfamily. GPCRs can be classified according to their structural and functional relationship, as represented by the ‘GPCR Tree’.

A Representation of the GPCR Tree Featuring of GPCRs Targeted by Tocris Products

ADRA1 ADRB3 HTR7 ADRB1 HTR2 S1PR LPAR HTR5

ADRB2 CNR1 CNR2 HTR1 Class A – Rhodopsin-like

ADRA2 DRD5 DRD1 MCR CHRM1 HTR6 CHRM1 CHRM1 CHRM1 ADORA2B ADORA2A CHRM1 HTR4 MLNR DRD2 TAR1 ADORA3 ADORA1 DRD4 DRD3 TBXA2R PTGFR HRH4 HRH3 EDNRB BRS3 GRPR OXTR PTGER1 EDNRA HRH2 HRH1 NMBR AVPR GNR PTGIR CCKAR HCRTR1 CCKBR PAR HCRTR CYSLTR NPFFR TACR2 GPR17 GPR35 GPR103 PTAFR EBI2 TRHR TACR1 P2YR NMUR NPYR TACR3 GPR55 MTLR NTSR MRGX1 (SNSR1) GHSR

BLTR

FPR1 UR2R MCHR GHRHR Class B – Secretin-like AGTRL1 GALR BDKBR SSTR SCTR CXCR GPR54 AGTR1 GPR7 CALCR VIPR CCR OPRL CRH1 PACAPR OPRK CRH1 GLPR OPRM CASR PTHR GIPR OPRD GABBR GRM5 GCGR GRM1 SMOH GRM2 GRM3 Class F – Frizzled GRM6 GRM4 GRM7 GRM8 Class C – Glutamate Adapted from Raymond et al (2013) Nat.Rev.Drug Discov. 12 25.

GPCR Tree Abbreviations ADORA, ; ADR, ; AGTR, receptor; AGTRL1, ; AVPR, ; BDKRB, ; BRS3, bombesin-like receptor 3; CALCR, ; CASR, calcium sensing receptor; CCKR, ; CCR, CC ; CHRM, acetylcholine muscarinic receptor; CNR, ; CRHR, corticotropin-releasing factor receptor; CXCR, CXC chemokine receptor; CYSLTR, cysteinyl ; DRD, ; EBI2, EBV-induced G-protein coupled receptor 2;

S1PR, sphingosine-1-phosphate receptor; EDNR, ; FPR, ; GABBR, GABAB receptor; GALR, ; GCGR, ; GHSR, ghrelin receptor; GIPR, GIP receptor; GLPR, glucagon-like receptor; GNRHR, gonadotropin-releasing ; GPR, G-protein coupled receptor; GRM, metabotropic; GRPR, -releasing peptide receptor; HCRTR, ; HRH, ; HTR, 5-HT receptor; LPAR, lysophosphatidic acid receptor; MCR, ; MCHR, melanin-concentrating hormone receptor; MRGX1 (SNSR1), -specific receptor;MLNR , ; MLNR, ; NMBR, neuromedin receptor; NMUR, receptor; NPFFR, neuropeptide FF receptor; NPYR, receptor; NTSR, ; OPR, , OXTR, ; P2YR, ; PACAPR, pituitary adenylate cyclase-activating polypeptide;

PAR, protease-activated receptor; PTAFR, platelet-activating factor receptor; PTGER, prostaglandin E2 receptor; PTGFR, prostaglandin F2 receptor; PTGIR; ; PTHR, receptor; SCTR, secretin receptor; SMOH, smoothened receptor; SSTR, ; TACR; ; TAR1, trace amine 1 receptor; TBXA2R, thromboxane A2 receptor; TRHR, thyrotropin-releasing hormone receptor; UR2R, urotensin receptor; VIPR, vasoactive intestinal peptide

tocris.com | 3 Tocris Product Listing Series Class A: Rhodopsin-like The Rhodopsin-like receptors are the largest class within the GPCR superfamily, being characterized by certain conserved residues in their transmembrane helices. Class A receptors have a wide variety of ligands including, , , glycoproteins, and lipids.

Category Cat. No. Product Name Description Unit Size

Class A1/A2: CC Chemokine Receptors Antagonists 3129 BMS CCR2 22 High affinity, potent CCR2 antagonist 1 mg 10 mg 50 mg 2595 J 113863 Potent CCR1 antagonist 1 mg 10 mg 50 mg 5176 JNJ 27141491 Potent and selective CCR2 antagonist 10 mg 50 mg 3756 Maraviroc Selective CCR5 antagonist 10 mg 50 mg 2089 RS 102895 CCR2b antagonist 10 mg 50 mg 2517 RS 504393 Highly selective CCR2 antagonist 10 mg 3650 SB 328437 Potent and selective CCR3 antagonist 10 mg 50 mg CXC Chemokine Receptors Agonists 4780 VUF 11207 Potent CXCR7 (ACKR3) 10 mg 50 mg 5668 VUF 11222 High affinity non-peptide CXCR3 agonist 10 mg 50 mg Antagonists 3299 AMD 3100 Highly selective CXCR4 antagonist 10 mg 50 mg 4179 AMD 3465 Potent, selective CXCR4 antagonist 10 mg 50 mg 4487 (±)-AMG 487 CXCR3 antagonist; inhibits cell migration and metastasis 10 mg 50 mg 5130 CTCE 9908 CXCR4 antagonist; antitumor 1 mg 4596 IT1t Potent CXCR4 antagonist 10 mg 50 mg

CXCR4 in Complex with IT1t Crystal Structure of the CXCR4 Homodimer in Complex with the CXCR4 Antagonist IT1t CXCR4 – IT1t 4596 H1 – 0508

Cat. No. 4596 O NH N S N N N

S

• IT1t binds to part of the binding cavity of CXCR4 and interacts with side chains from helices I, II, III and VII • IT1tB2- isA da rpotentenerg CXCR4ic – ICI antagonist118,551 (IC 0821 = 1.1 nM) Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3OE9 50 CRF1R – CP-376395 3212 Wu et al (2010) Science 330 1066. PMID 20929726. • The compound is orally available

4 | N

O O N H

N HO H

A2A – ZM 241385 1036 MGLUR1 – LY 341495 1209

OH NH2 O

O N N N

N N N H2N H CO2H OH O

D3 – Eticlopride 1847

HO O

N N H O Cl GPCR research Class A: Rhodopsin-like – continued GPCR Crystal Structures Crystallography refers to the study of atomic and molecular structure. The elucidation of molecular structures of membrane such as GPCRs has proven problematic, and only a small fraction of known GPCRs have been solved to date. GPCR crystal structures are invaluable for structure-based drug discovery approaches.

GPCR Crystal Structures and Drug Discovery: The solving of GPCR crystal structures has been notoriously difficult, due to their flexible conformations. For their structure to be solved GPCRs need to be embedded in a membrane-like environment to maintain their structural integrity. This was difficult to achieve until the last decade, when certain mutations were found to increase GPCR stability and expression levels, while stabilization antibodies can also enhance GPCR stability. The first GPCR structure to be crystallized was the Rhodopsin receptor in 2000, and receptor stabilization techniques resulted

in the discovery of the and adrenergic β1 and β2 receptors in 2008. To date 26 GPCR structures have been solved (see table below). GPCR crystal structures could prove to be essential for next generation drug discovery. These structures can be utilized by automated computational screens for the identification of novel ligands and chemotypes, which could produce lead compounds for the synthesis of next generation drugs and enhanced therapeutics.

GPCR Species PDB-ID Reference

Acetylcholine Muscarinic M2 Receptor Human Iperoxo 4MQS Kruse et al (2013) Nature 504 101

Acetylcholine Muscarinic M3 Receptor Rat Tiotropium (#5902) 4U15 Thorsen et al (2014) Structure 22 1657 Adenosine (#3624) 2YDO Jaakola et al (2008) Science 322 1211

Adenosine A2A Receptor Human NECA (#1691) 2YDV Lebon et al (2011) Nature 474 521 ZM 241385 (#1036) 3EML (#0993) 2VT4 (#0515) 2Y00 Adrenergic β Receptor Turkey Warne et al (2008) Nature 454 486 1 (#1747) 2Y03 (#0634) 2Y04 ICI 118,551 (#0821) 3NY8 Wacker et al (2010) J.Am.Chem.Soc 132 11443 Adrenergic β2 Receptor Human (#0649) 3D4S Hanson et al (2008) Structure 16 897 Chemokine CCR5 Receptor Maraviroc (#3756) 4MBS Tan et al (2013) Science 341 1387 Chemokine CXCR1 Receptor Human - 2LNL Park et al (2012) Nature 491 779 Chemokine CXCR4 Receptor Human IT1t (#4596) 3OE6 Wu et al (2010) Science 330 1066 Corticotropin-releasing Factor Receptor 1 CP 376395 (#3212) 4K5Y Hollenstein et al (2013) Nature 499 438

Dopamine D3 Receptor Human Eticlopride (#1847) 3PBL Chien et al (2010) Science 330 1091 1 TAK-875 4PHU Srivastava et al (2014) Nature 513 124 Glucagon Receptor Human - 4L6R Siu et al (2013) Nature 499 444

Histamine H1 Receptor Human Doxepin (#0508) 3RZE Shimamura et al (2011) Nature 475 65

5-HT1B (#0475) 4IAQ Wang et al (2013) Science 340 610

5-HT2B 4IB4 Wacker et al (2013) Science 340 615 Metabotropic Glutamate Receptor 1 LY 341495 (#1209) 3KS9 Dobrovetsky et al (Data yet to be published) Neurotensin Receptor Neurotensin (#1909) 4GRV White et al (2012) Nature 490 508 κ Opioid Receptor Human JDTic 4DJH Wu et al (2012) Nature 485 327 μ Opioid Receptor β-Funaltrexamine (#0926) 4DKL Manglik et al (2012) Nature 485 321 δ Opioid Receptor (#0740) 4EJ4 Granier et al (2012) Nature 485 400

OX2 Orexin Receptor Human 4S0V Yin et al (2015) Nature 519 247 Protease-activated Receptor 1 Human Vorapaxar 3VW7 Zhang et al (2012) Nature 492 387

Purinergic Receptor 2MeSADP (#1624) 4PXZ Zhang et al (2014) Nature 509 119 Rhodopsin Receptor Bovine 11-cis-Retinal 1F88 Palczewski et al (2000) Science 289 739 (#1623) 4O9R Wang et al (2014) Nat.Commun. 5 4355 Smoothened Receptor Human SANT-1 (#1974) 4N4W Weierstall et al (2014) Nat.Commun. 5 3309 Sphingosine-1 Phosphate Receptor ML 056 (3602) 3V2W Hanson et al (2012) Science 335 851

GPCR Crystal Structure Table Table listing GPCRs whose crystal structures have been solved to date. Where the structure has been solved in complex with a ligand, the ligand is also listed. Ligands in bold are available from Tocris. The PDB-ID is the crystal structures PDB-ID from the RCSB PDB (www.rcsb.org/pdb). Data from zhanglab.ccmb.med.umich.edu/GPCR-EXP.

tocris.com | 5 Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size 4528 (±)-NBI 74330 Potent and selective CXCR3 antagonist 10 mg 5660 NVP CXCR2 20 Potent and selective CXCR2 antagonist 10 mg 50 mg 2725 SB 225002 Potent and selective CXCR2 antagonist 10 mg 50 mg 2724 SB 265610 Potent CXCR2 antagonist 1 mg 10 mg 50 mg 4300 TC 14012 CXCR4 antagonist; also CXCR7 (ACKR3) agonist 1 mg

Class A2 (GPER) Receptors Agonists 3577 G-1 Potent and selective GPER agonist 10 mg 50 mg 1047 ICI 182,780 High affinity GPER agonist 1 mg 10 mg 50 mg Antagonists 3678 G-15 High affinity and selective GPER antagonist 10 mg 50 mg

Class A3 Angiotensin Receptors Agonists 1158 Angiotensin II Potent vasoconstrictor peptide 5 mg

5728 EXP 3174 Potent and selective AT1 antagonist 10 mg 50 mg

Antagonists 5798 Irbesartan Potent AT1 antagonist 50 mg

3798 Losartan potassium Selective, non-peptide AT1 antagonist 50 mg

1361 PD 123319 Potent, selective non-peptide AT2 antagonist 10 mg 50 mg Apelin (APJ) Receptors Agonists 2420 [Pyr1]-Apelin-13 Potent peptide agonist for APJ receptor 1 mg 3007 Apelin-17 (human, bovine) Endogenous APJ receptor agonist 1 mg 2426 Apelin-36 (human) Endogenous APJ receptor agonist 1 mg Antagonists 4748 ML 221 APJ 10 mg 50 mg Bradykinin Receptors

Agonists 3004 Bradykinin Endogenous agonist at bradykinin receptors (B2 > B1) 5 mg

Antagonists 3014 HOE 140 Potent and selective B2 antagonist 500 µg Class A4 δ Opioid Receptor Agonists 0764 SNC 80 Highly selective non-peptide δ agonist 10 mg 50 mg Antagonists 0740 Naltrindole Selective non-peptide δ antagonist 10 mg 50 mg κ Opioid Receptor Agonists 3195 A Endogenous κ agonist 1 mg 5519 (-)- κ agonist; antinociceptive 10 mg 0496 (-)-U-50488 Standard selective κ agonist; more active enantiomer of 10 mg (±)-U-50488 (Cat. No. 0495) 50 mg 0495 (±)-U-50488 Standard selective κ agonist 25 mg Antagonists 0347 nor- Standard selective κ antagonist 10 mg 50 mg

6 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size μ Opioid Receptor Agonists 1171 DAMGO Selective μ agonist 1 mg Antagonists 1560 CTAP Selective and potent μ antagonist 1 mg 2601 Selective μ antagonist 10 mg 0926 β-Funaltrexamine Irreversible μ-selective antagonist 10 mg 50 mg Opioid Receptors (Non-selective) Agonists 5158 Morphine opioid 50 mg 1419 benzoylhydrazone Full κ agonist; partial μ and δ agonist 10 mg 50 mg Antagonists 0599 Naloxone Broad spectrum opioid receptor antagonist 100 mg 0677 Broad spectrum opioid receptor antagonist 100 mg Neuropeptide W/B Receptors Agonists 3009 Neuropeptide W-23 (human) Endogenous NPBW1 and NPBW2 agonist 1 mg Antagonists 4948 CYM 50769 Novel non-peptide NPBWR1 antagonist 10 mg 50 mg Somatostatin (sst) Receptors

Agonists 1979 L-803,087 Potent and selective sst4 agonist 10 mg

1818 sst2, sst3 and sst5 agonist 1 mg 1157 Somatostatin Influences release 1 mg Antagonists 3493 Cyclosomatostatin Non-selective sst receptor antagonist 1 mg

1843 CYN 154806 Selective sst2 antagonist 1 mg Class A5 Galanin Receptors Agonists 2696 Galanin (1-29) (rat, mouse) Non-selective galanin receptor agonist 1 mg 1179 Galanin (1-30) (human) Endogenous galanin receptor agonist 200 µg Kisspeptin Receptor Agonists 2570 Kisspeptin 10 (human) Endogenous kisspeptin receptor ligand 1 mg 4243 Kisspeptin 10 (rat) Endogenous kisspeptin receptor ligand 1 mg Leukotriene Receptors

Agonists 2307 BLT1/BLT2 receptor agonist and potent chemotactic factor 50 µg

Antagonists 2338 MK 571 Potent CysLT1 (LTD4) ; also MRP1 inhibitor 10 mg Other 1311 MK 886 Inhibitor of 5-lipoxygenase-activating protein (FLAP) 10 mg 50 mg Melanin-concentrating Hormone (MCH) Receptors Agonists 3806 MCH (human, mouse, rat) Potent endogenous MCH receptor agonist 100 µg

Antagonists 4242 GW 803430 MCH1 antagonist 10 mg 50 mg

4365 TC-MCH 7c Selective MCH1 antagonist 10 mg Urotensin-II (UT) Receptor Agonists 2484 (±)-AC 7954 Non-peptide UT receptor agonist 10 mg 50 mg 1642 Urotensin II (human) Endogenous vasoactive agonist for the UT receptor 1 mg Antagonists 5110 GSK 1562590 High affinity, selective UT receptor antagonist 10 mg 50 mg 3571 SB 657510 Selective UT receptor antagonist 10 mg 50 mg 4667 SB 706375 High affinity, non-peptide UT receptor antagonist 10 mg 50 mg

tocris.com | 7 Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size

Class A6 Cholecystokinin (CCK) Receptors

Agonists 2411 A-71623 Potent and selective CCK1 agonist; suppresses feeding 1 mg 1166 CCK Octapeptide, sulfated C-terminal octapeptide of CCK 1 mg

3006 Gastrin I (human) Selective CCK2 agonist 1 mg

Antagonists 2607 CI 988 Potent and selective CCK2 antagonist 10 mg 50 mg

2304 Selective CCK1 antagonist; orally active 10 mg 50 mg Gonadotropin-releasing Hormone (GnRH) Receptor Agonists 3592 Goserelin GnRH receptor agonist 10 mg Antagonists 3536 Cetrorelix Potent GnRH receptor antagonist 1 mg 2519 T 98475 GnRH receptor antagonist 1 mg GPR103 Ligands 4402 26RFa Ligand of GPR103; orexigenic neuropeptide 1 mg Orexin Receptors

Agonists 1455 Orexin A (human, rat, mouse) Endogenous agonist at OX1 and OX2 500 µg 11 15 2142 [Ala ,D-Leu ]-Orexin B Potent, selective OX2 receptor agonist 1 mg

1456 Orexin B (human) Endogenous agonist at OX1 and OX2 500 µg

1457 Orexin B (mouse) Endogenous agonist at OX1 and OX2 500 µg

Antagonists 4983 ACT 335827 Potent and selective OX1 antagonist 10 mg 50 mg 5319 ACT 462206 Potent, dual orexin receptor antagonist 10 mg 50 mg

4558 EMPA Highly potent and selective OX2 antagonist; penetrant 10 mg 50 mg

5645 IPSU OX2 receptor antagonist; orally bioavailable and brain penetrant 10 mg

4317 JNJ 10397049 Selective OX2 receptor antagonist 10 mg 50 mg

Featured Orexin Receptor Antagonists

OMe O

N N N HN O S O O N N S O O O

ACT 462206 (5319) EMPA (4558)

Potent, dual orexin receptor antagonist Highly potent and selective OX2 antagonist; brain penetrant

F O N N NH N S N O O N N N O N

SB 674042 (4673) IPSU (5645)

Potent and selective non-peptide OX1 antagonist OX2 antagonist; orally bioavailable and brain penetrant

Orexin Receptors 8 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size

1960 SB 334867 Selective non-peptide OX1 antagonist 1 mg 10 mg 50 mg

4673 SB 674042 Potent and selective non-peptide OX1 antagonist 10 mg 50 mg

3371 TCS OX2 29 Potent and selective OX2 antagonist 10 mg 50 mg Oxytocin Receptor Agonists 1910 Oxytocin Endogenous oxytocin receptor agonist 1 mg 3933 WAY 267464 Potent non-peptide oxytocin receptor agonist 10 mg Antagonists 2641 L-368,899 Potent, non-peptide oxytocin receptor antagonist 1 mg 10 mg 2410 L-371,257 Potent and selective oxytocin receptor antagonist 10 mg Vasopressin Receptors

F Antagonists 2310 SR 49059 Selective, orally active V1A receptor antagonist 10 mg F S 5181 Tolvaptan Potent and selective V receptor antagonist; renoprotective and orally 10 mg NH 2 active 50 mg N O N Class A7 O OMe Bombesin Receptors O N Agonists 5600 BA 1 Potent BRS-3 agonist; also NMBR and GRPR agonist 1 mg 1789 GRP (human) Endogenous GRP receptor agonist 1 mg JNJ 27141491 (Cat. No. 5176) NH Antagonists 5599 ML 18 BRS-3 antagonist; also GRPR agonist 10 mg N Endothelin (ET) Receptors N

Agonists 1189 BQ-3020 Selective ETB agonist 500 µg O N N 1160 (human, porcine) Endogenous endothelin receptor agonist 100 µg Antagonists 1188 BQ-123 Selective ET antagonist 500 µg OMe N NH A 1500 BQ 788 sodium salt Selective ETB antagonist 1 mg 1838 IRL-2500 Potent ET antagonist 10 mg Br B Ghrelin Receptor Purmorphamine (4551) F Agonists 1463 Ghrelin (human) Endogenous ghrelin receptor agonist 1 mg 1465 Ghrelin (rat) Endogenous ghrelin receptor agonist 1 mg ML 00253764 (4854) 5272 MK 0677 High affinity ghrelin receptor agonist 10 mg 50 mg Antagonists 1922 [D-Lys3]-GHRP-6 Ghrelin receptor antagonist 5 mg 3959 YIL 781 F3C Ghrelin receptor (GHS-R1a) antagonist 10 mg H 50 mg N N Motilin ReceptorN N N H O Agonists 2264 NMotilinN (human, porcine) Endogenous motilin receptor agonist 1 mg Antagonists 5074 ANQ 11125 Selective motilin receptor antagonist 1 mg Cl N 4934 MA 2029CMPD101 (5642) Potent and selective motilin receptor antagonist; 10 mg O O N N N orally active 50 mg H H S N H Potent and Selective Motilin Receptor Antagonist

TC-G 1008 (5355) MA 2029 Cat. No. 4934

F O NH HN O MA 2029 is a potent and selective motilin receptor antagonist N (IC50 = 4.9 nM) that exhibits selectivity for the motilin receptor N over a range of other receptors and ion channels. The compound H O inhibits motilin-induced colonic and abdominal contractions in vivo. MA 2029 is also orally active. HN N O OH

NH2 N MA 2029 (4934) O tocris.com | 9 Br HN HN N N N HO O O

Br

BIBN 4096 (4561) Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size Neuromedin U (NMU) Receptors

Agonists 3648 (rat) Potent, endogenous NMU1 and NMU2 agonist 500 µg 1917 Neuromedin U (rat) Endogenous modulator of and flow, gut ion transport, 1 mg feeding and body temperature Neurotensin (NTS) Receptors Agonists 1909 Neurotensin Endogenous neurotensin receptor agonist 1 mg

5087 TC NTR1 17 Selective non-peptide NTS1 agonist 10 mg 50 mg Antagonists 2309 SR 142948 Highly potent NT receptor antagonist 1 mg 10 mg

3721 SR 48692 Selective non-peptide NTS1 antagonist 10 mg 50 mg Thyrotropin-Releasing Hormone Receptors Agonists 2672 Synthetic thyrotropin-releasing hormone analog 1 mg 10 mg

Class A8 Formyl Peptide Receptors (FPRs) Agonists 5583 Quin C1 Potent and selective FPR2 agonist 10 mg 50 mg 4624 TC-FPR 43 Potent FPR2 agonist 10 mg 50 mg Antagonists 2262 WRW4 Selective FPR2 antagonist 1 mg Class A9 Melatonin (MT) Receptors Agonists 0737 2-Iodomelatonin High affinity melatonin receptor agonist 10 mg 50 mg 0680 2-Phenylmelatonin Potent melatonin receptor agonist 10 mg 50 mg

Antagonists 0877 MT1/MT2 antagonist 10 mg 50 mg

1034 4-P-PDOT MT2 antagonist 10 mg 50 mg Neuropeptide Y (NPY) Receptors Agonists 1153 Neuropeptide Y (human, rat) Endogenous NPY receptor agonist 200 µg

Antagonists 2412 BIBO 3304 Highly selective NPY Y1 receptor antagonist 10 mg 50 mg

2707 BIBP 3226 Mixed NPY Y1 and NPFF receptor antagonist 1 mg 10 mg

1700 BIIE 0246 Potent, selective non-peptide NPY Y2 receptor antagonist 1 mg 10 mg

4018 JNJ 5207787 Selective NPY Y2 receptor antagonist 10 mg 50 mg Tachykinin (NK) Receptors

Agonists 1668 GR 64349 Potent, selective NK2 agonist 1 mg

1669 GR 73632 Potent, selective NK1 agonist 1 mg

1068 Senktide Tachykinin NK3 agonist 500 µg

Antagonists 1274 GR 159897 Non-peptide, potent NK2 antagonist 10 mg 50 mg

1145 L-733,060 Potent NK1 antagonist 10 mg 50 mg

1635 RP 67580 Potent and selective NK1 antagonist 10 mg 50 mg

4672 SB 223412 Potent, selective non-peptide NK3 antagonist; brain penetrant 10 mg 50 mg

10 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size

Class A11 Free Fatty Acid (FFA) Receptors

Agonists 5257 GSK 137647 Potent and selective FFA4 (GPR120) agonist 10 mg 50 mg

4601 TUG 891 Potent and selective FFA4 (GPR120) agonist 10 mg 50 mg

Antagonists 5256 AH 7614 Selective FFA4 (GPR120) antagonist 10 mg 50 mg

5357 DC 260126 FFA1 (GPR40) antagonist 10 mg 50 mg Hydroxycarboxylic Acid (HCA) Receptors

Agonists 1762 Acifran GPR109A (HCA2) and GPR109B agonist; hypolipidemic agent 10 mg 50 mg

4599 3,5-DHBA Selective HCA1 agonist 50 mg

4622 MK 1903 Potent and selective GPR109A (HCA2) agonist 10 mg 50 mg

Class A11/12 Purinergic (P2Y) Receptors Agonists 3245 ATP P2 agonist 50 mg 3209 α,β-Methyleneadenosine P2 agonist 10 mg 5ʹ-triphosphate trisodium salt

1624 2-Methylthioadenosine diphosphate Potent agonist for P2Y1, P2Y12 and P2Y13 10 mg

2157 MRS 2365 Highly potent and selective P2Y1 agonist 1 mg

2915 MRS 2690 Potent P2Y14 agonist 1 mg

2502 MRS 2693 trisodium salt Selective P2Y6 agonist 1 mg

3884 MRS 2768 tetrasodium salt Selective P2Y2 agonist 1 mg

4261 MRS 4062 Selective P2Y4 agonist 1 mg

2715 PSB 0474 Potent and selective P2Y6 agonist 1 mg

4333 PSB 1114 Potent, selective P2Y2 agonist 1 mg

3280 2-ThioUTP tetrasodium salt Potent and selective P2Y2 agonist 1 mg

3279 UTPγS trisodium salt Selective P2Y2/4 agonist 1 mg

Antagonists 4890 AR-C 118925XX Selective, competitive P2Y2 antagonist 5 mg

3321 AR-C 66096 tetrasodium salt Potent and selective P2Y12 antagonist 1 mg

1820 (+)-Clopidogrel Selective P2Y12 antagonist 10 mg 50 mg

5316 Elinogrel P2Y12 antagonist 10 mg 50 mg

0900 MRS 2179 tetrasodium salt Selective P2Y1 antagonist 10 mg 50 mg

Featured Free Fatty Acid Receptor Agonists and Antagonists

CO H 2 O S O O HN O S O N H

O O F GSK 137647 (5257) TUG 891 (4601) AH 7614 (5256)

Potent and selective FFA4 (GPR120) agonist Potent and selective FFA4 Selective FFA4 (GPR120) antagonist (GPR120) agonist

tocris.com | 11 Free Fatty Acid Receptors Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size

2402 MRS 2211 Competitive P2Y13 antagonist 10 mg 50 mg

2158 MRS 2279 Selective, high affinity P2Y1 antagonist 1 mg

2159 MRS 2500 Extremely potent and selective P2Y1 antagonist 1 mg

2146 MRS 2578 Selective P2Y6 antagonist 10 mg 50 mg

3830 NF 340 Selective P2Y11 antagonist 10 mg

3983 PSB 0739 Highly potent P2Y12 antagonist 10 mg 50 mg

Class A12 Platelet-activating Factor (PAF) Receptor Agonists 3022 Edelfosine PAF receptor agonist 10 mg 2940 PAF (C16) Endogenous PAF receptor agonist 1 mg Antagonists 2339 WEB 2086 Potent PAF receptor antagonist 1 mg 10 mg

Class A13 Cannabinoid (CB) Receptors

Agonists 2928 CB 13 Potent dual CB1/CB2 agonist 10 mg 50 mg

2764 GP 1a Highly selective CB2 agonist 10 mg 50 mg

3088 HU 308 Potent and selective CB2 agonist 10 mg 50 mg

Antagonists 1117 AM 251 Potent CB1 antagonist; also GPR55 agonist 1 mg 10 mg 50 mg

1115 AM 281 Potent, selective CB1 antagonist/inverse agonist 10 mg 50 mg

1120 AM 630 CB2 selective antagonist/inverse agonist 10 mg 50 mg

1570 (-)- Natural cannabinoid; GPR55 antagonist, weak CB1 antagonist 10 mg and CB2 inverse agonist 50 mg

2479 JTE 907 Selective CB2 receptor antagonist/inverse agonist 10 mg 50 mg

4605 (±)-SLV 319 Potent and selective CB1 receptor antagonist 10 mg 50 mg

Modulators 5321 PSNCBAM-1 CB1 receptor negative 10 mg 50 mg

Antagonists 0923 SR 141716A Selective CB1 receptor antagonist 10 mg 50 mg Other 1445 N-Arachidonylglycine Endocannabinoid; suppresses in vivo 5 mg 25 mg 2540 Tocrifluor T1117 Novel fluorescent cannabinoid ligand; fluorescent form of 100 µg AM 251 (Cat. No. 1117)

12 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size Melanocortin (MC) Receptors

Agonists 3492 ACTH (1-39) Potent endogenous MC2 agonist 1 mg

4053 BMS 470539 Potent, selective MC1 receptor agonist 10 mg 50 mg 3013 [Nle4,D-Phe7]-α-MSH Melanocortin receptor agonist 1 mg

3032 THIQ Potent and selective MC4 receptor agonist 1 mg

Antagonists 4854 ML 00253764 Melanocortin MC4 receptor antagonist; brain penetrant 10 mg 50 mg

4919 PG 106 Selective MC3 receptor antagonist 1 mg Sphingosine-1-phosphate Receptors

Agonists 3601 CYM 5442 Selective S1P1 receptor agonist 10 mg 50 mg

5418 CYM 5520 Selective S1P2 allosteric agonist 10 mg 50 mg

4897 CYM 5541 Selective S1P3 receptor allosteric agonist 10 mg 50 mg

1370 Sphingosine-1-phosphate Endogenous agonist at S1P1-5 1 mg

Antagonists 4679 CYM 50358 Potent and selective S1P4 antagonist 10 mg 50 mg

2392 JTE 013 S1P2 receptor antagonist 10 mg

5328 TY 52156 S1P3 receptor antagonist 10 mg 50 mg

4195 VPC 23019 S1P1 and S1P3 antagonist 10 mg

3602 W146 Potent and selective S1P1 receptor antagonist 1 mg Class A13/15 Lysophosphatidic Acid (LPA) Receptors

Agonists 4779 GRI 977143 Selective LPA2 non-lipid agonist 10 mg 50 mg

Antagonists 4878 H2L5186303 Potent and selective LPA2 antagonist 10 mg F 50 mg F S 5056 Ki 16425 NH LPA1 and LPA3 antagonist 10 mg N 50 mg O N 4708 TC LPA5 4 LPA5 antagonist O 10 mg OMe 50 mg O N

JNJ 27141491 (Cat. No. 5176) NH

Melanocortin MC Receptor Antagonist N 4 N ML 00253764 Cat. No. 4854 O N N

ML 00253764 is a non-peptide MC receptor antagonist (IC values are OMe N NH 4 50 320, 810 and 2120 nM for MC4, MC3 and MC5 receptors, respectively). The compound increases food intake and reduces loss of body mass Br in tumor bearing mice. ML 00253764 is alsoPurmorphamine brain penetrant. (4551) F

ML 00253764 (4854)

F3C H N N N N N H O N N

Cl N CMPD101 (5642)

O O N N N H H S tocris.com | 13 N H

TC-G 1008 (5355)

F O NH HN O N N H O

HN N O OH

NH2 N MA 2029 (4934) O Br HN HN N N N HO O O

Br

BIBN 4096 (4561) Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size Class A14 Prostanoid Receptors Agonists 1620 Alprostadil Prostaglandin; vasodilator and antiplatelet agent in vivo 10 mg 50 mg 4180 Beraprost sodium Potent prostacyclin IP receptor agonist 1 mg

2295 (±)-Cloprostenol sodium salt Water-soluble PGF2α analog and potent FP receptor agonist 10 mg

2038 Iloprost Prostacyclin (PGI2) analog 1 mg

2296 Prostaglandin E2 Major endogenous prostanoid 10 mg

4214 Prostaglandin F2α Naturally-occurring prostanoid; potent vasoconstrictor 10 mg

3351 Selexipag Selective prostacyclin IP1 receptor agonist 10 mg 50 mg

5349 Treprostinil Potent prostacyclin (PGI2) analog 10 mg

Antagonists 2514 L-161,982 Selective EP4 antagonist 10 mg

3342 L-798,106 Potent and highly selective EP3 antagonist 10 mg 50 mg

5406 ONO 8130 EP1 antagonist 10 mg 50 mg

3565 ONO AE3 208 High affinity and selective EP4 antagonist 10 mg 50 mg

4818 PF 04418948 Potent and selective EP2 antagonist 10 mg 50 mg 4268 Ro 1138452 Selective prostacyclin IP antagonist 10 mg 50 mg

5052 TG 4-155 High affinity and selective EP2 antagonist 10 mg 50 mg Thromboxane (TP) Receptors

Agonists 1932 U 46619 Potent, stable thromboxane A2 (TP) receptor agonist 1 mg

Antagonists 5568 S 18886 Potent thromboxane A2 (TP) receptor antagonist 10 mg Class A15 GPR35 Agonists 4298 Pamoic acid disodium salt GPR35 agonist 50 mg Antagonists 4293 CID 2745687 GPR35 antagonist 10 mg 50 mg 4172 ML 145 GPR35 antagonist 10 mg 50 mg Protease-activated Receptors (PARs)

Agonists 3015 2-Furoyl-LIGRLO-amide Potent and selective PAR2 agonist 1 mg

3010 SLIGKV-NH2 PAR2 agonist 5 mg

1468 SLIGRL-NH2 PAR2-activating peptide 1 mg

1464 TFLLR-NH2 PAR1-activating peptide 1 mg

3497 TRAP-6 PAR1 peptide fragment (residues 42-47); acts as 5 mg a PAR1 agonist

Antagonists 4751 FSLLRY-NH2 PAR2 peptide antagonist 1 mg

5387 ML 354 Selective PAR4 antagonist 10 mg 50 mg

1592 SCH 79797 Potent, selective non-peptide PAR1 antagonist 10 mg 50 mg

1488 tcY-NH2 Selective PAR4 antagonist 1 mg

14 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size Class A17 α Adrenergic Receptors

Agonists 1052 A 61603 α1A agonist 10 mg 50 mg

0888 Selective α1 agonist 10 mg

2749 Potent, highly selective α2 agonist; active isomer of 10 mg (Cat. No. 5160) 50 mg 0475 Dihydroergotamine Partial α agonist; non-selective 100 mg 5169 Noradrenaline Endogenous adrenergic hormone and 50 mg

Antagonists 0986 Highly selective α2B antagonist 10 mg 50 mg β Adrenergic Receptors

Agonists 0948 BRL 37344, sodium salt β3 agonist 10 mg 50 mg

1499 CL 316243 Highly selective β3 agonist 10 mg 50 mg

0515 Dobutamine β1 and β2 agonist 50 mg

1448 Potent and selective β2 agonist 10 mg 50 mg 1747 Isoproterenol Standard selective β agonist 100 mg

2197 L-755,507 Very potent and selective β3 partial agonist 10 mg 50 mg 0634 Salbutamol Non-selective β- 250 mg

0950 β1 selective partial agonist 10 mg 50 mg CXCR4 – IT1t 4596 H1 – Doxepin 0508 Antagonists 0906 Selective β1 antagonist 10 mg 50 mg

2685 β-adrenoceptor and α1-adrenoceptor antagonist 50 mg

1024 CGP 20712 Highly potent and selective β1 antagonist 10 mg 50 mg O

0993 Cyanopindolol β-adrenergic receptor antagonist; also 5-HT1A/1B antagonistNH 10 mg N S 50 mg N 0821 ICI 118,551 Very selective β2 antagonistN N 10 mg 50 mg S

β2 Adrenergic Receptor in Complex with ICI 118,551

Crystal Structure of the β2 Adrenergic Receptor in Complex with the β2 Antagonist ICI 118,551

Intracellular Membrane Extracellular B2-Adrenergic – ICI 118,551 0821 CRF1R – CP-376395 3212

N Cat. No. 0821 O O N H

N HO H

• ICI 118,551 binds to the orthosteric binding site of β2

• ICI 118,551 is a selective β2 antagonist that exhibits Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3NY8 selectivity for β2 over β1 and β3 receptors Wacker et al (2010) J.Am.Chem.Soc. 132 11443. PMID 20669948. • The compoundA2A – ZM is 241385 active in vivo1036 MGLUR1 – LY 341495 1209

OH tocris.com | 15 NH2 O

O N N N

N N N H2N H CO2H OH O

D3 – Eticlopride 1847

HO O

N N H O Cl Tocris Product Listing Series CXCR4 – IT1t 4596 H1 – Doxepin 0508

O Category Cat. No. Product Name Description Unit Size NH N 2760 L-748,337 Selective antagonist 10 mg β3 S N N N 50 mg

1511 SR 59230A Potent and selective β3 antagonist 10 mg S 50 mg

0649 (S)-Timolol β1 antagonist 100 mg

Dopamine D1/D5 Receptors

Agonists 1701 A 77636 Potent, selective D1-like agonist; orally active 10 mg 50 mg

0884 Selective D1-like agonistB2-Adrenergic – ICI 118,551 0821 5 mg 25 mg CRF1R – CP-376395 3212

0922 SKF 38393 Selective D1-like agonist 100 mg

1447 SKF 81297 D1 agonist 10 mg 50 mg N 2074 SKF 83959 D1-like partial agonist 10 mg O 50 mg O N H Antagonists 0925 SCH 23390 Standard selective D1-like antagonist; also 5-HT2C and 10 mg 5-HT1C agonist 50 mg H N 2299 SCH 39166 High affinity 1D /D5 antagonist O H 10 mg 50 mg

1586 SKF 83566 Potent, selective D1-like antagonist 10 mg 50 mg

Dopamine D2/D3/D4 Receptors 4552 A 412997 Selective D agonist 10 mg Agonists 4 A2A – ZM 241385 1036 50 mg MGLUR1 – LY 341495 1209

1243 (+)-PD 128907 D3 agonist (D3 ≥ D2 > D4) 10 mg 50 mg

1065 PD 168077 High affinity, selective D4 agonist OH 10 mg NH O 2 50 mg O N 2773 D2-selective agonist N N 10 mg 50 mg N N N H2N Antagonists 1847 Eticlopride Selective D2/D3 antagonist H 10 mg CO2H 50 mg OH O 1003 L-741,626 High affinity D2 antagonist 10 mg 50 mg

D3 Dopamine Receptor in Complex with Eticlopride D3 – Eticlopride 1847

Crystal Structure of the D3 Dopamine Receptor in Complex with the D3/D2 Antagonist Eticlopride

Extracellular HO O

N N Cat. No. 1847 H Membrane O Cl

Intracellular

• Eticlopride binds to part of the D3 binding pocket defined by side chains of helices III, V, VI and VII.

• Eticlopride is a selective D3/D2 receptor antagonist Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3PBL (Ki values are 160 and 500 nM, respectively) Chien et al (2010) Science 330 1091. PMID 21097933. • The compound is an

16 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size

1004 L-741,742 Highly selective D4 antagonist 10 mg 50 mg

1002 L-745,870 Highly selective D4 antagonist 10 mg 50 mg

4207 SB 277011A Selective D3 antagonist 10 mg 50 mg Dopamine Receptors (Non-selective) Agonists 2073 (R)-(-)- ; non-subtype-selective 50 mg

Antagonists 1847 Eticlopride Selective D2/D3 antagonist 10 mg 50 mg

Trace Amine 1 Receptor (TA1)

Agonists 5252 TA1 agonist 50 mg

Antagonists 4518 EPPTB TA1 antagonist/inverse agonist 10 mg 50 mg

Class A17/18 Histamine Receptors

Agonists 0646 HTMT H1 / H2 agonist 10 mg 50 mg

0569 (R)-(-)-α-Methylhistamine Potent, standard H3 agonist 10 mg 50 mg

2342 4-Methylhistamine Selective, high affinity H4 agonist 10 mg 50 mg

2478 2-Pyridylethylamine H1 receptor agonist 50 mg

Antagonists 3489 Orally active, potent ; also KV11.1 (hERG) 50 mg

3743 BF 2649 H3 receptor inverse agonist/antagonist 10 mg 50 mg

0508 Doxepin Highly potent H1 antagonist; also binds to H4 receptor 1 g

4021 JNJ 7777120 Selective H4 receptor antagonist 10 mg 50 mg

0660 Selective H1 inverse agonist 100 mg

1070 Potent, centrally active H2 antagonist 10 mg 50 mg

H1 Histamine Receptor in Complex with Doxepin

Crystal Structure of the H1 Histamine Receptor in Complex with the H1 Antagonist Doxepin

IntracellularCXCR4 – IT1tMembrane 4596 Extracellular H1 – Doxepin 0508

O Cat. No. 0508 NH N S N N N

S • Doxepin binds deep in the H1 binding pocket defined by side chains of helices III, V and VI, and interacts with the Trp4286.48 residue

• Doxepin is a high affinity H1 receptor antagonist Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3RZE (Kd = 310 pM) Shimamura et al (2011) Nature 475 65. PMID 21697825. • The compound is a B2-Adrenergic – ICI 118,551 0821 CRF1R – CP-376395 3212

tocris.com | 17 N

O O N H

N HO H

A2A – ZM 241385 1036 MGLUR1 – LY 341495 1209

OH NH2 O

O N N N

N N N H2N H CO2H OH O

D3 – Eticlopride 1847

HO O

N N H O Cl Tocris Product Listing Series

Category Cat. No. Product Name Description Unit Size

Class A17/19

5-HT1 Receptors

Agonists 1317 CP 94253 Potent, selective 5-HT1B agonist 10 mg 50 mg

0529 8-Hydroxy-DPAT Selective 5-HT1A agonist; also has moderate affinity 10 mg for 5-HT7 50 mg

3079 LY 334370 Selective 5-HT1F agonist 10 mg 50 mg

1985 PNU 142633 Highly selective 5-HT1D agonist 10 mg

Antagonists 1477 GR 127935 Potent, selective 5-HT1B/1D antagonist 10 mg 50 mg

1054 GR 55562 5-HT1B antagonist 10 mg 50 mg

1242 SB 216641 Selective h5-HT1B antagonist 10 mg 50 mg

1221 SB 224289 Selective 5-HT1B antagonist 10 mg 50 mg

1253 (S)-WAY 100135 Potent, selective 5-HT1A antagonist 10 mg 50 mg

4380 WAY 100635 Potent, 5-HT1A silent antagonist; also D4 agonist 10 mg 50 mg

5-HT2 Receptors

Agonists 1059 BW 723C86 5-HT2B agonist 10 mg 50 mg

5171 NBOH--CN High affinity, selective 5-HT2A agonist 10 mg 50 mg

1854 Ro 60-0175 Potent, selective 5-HT2C agonist 10 mg 50 mg

2592 TCB-2 Potent, high affinity 5-HT2A agonist 10 mg 50 mg

Antagonists 4173 MDL 100907 Potent and selective 5-HT2A antagonist 10 mg 50 mg

1644 5-HT2A and 5-HT2C antagonist; also dopamine receptor 10 mg partial agonist 50 mg

1955 Potent 5-HT2 antagonist 10 mg 50 mg

2993 RS 127445 Selective, high affinity 5-HT2B antagonist 10 mg 50 mg

1661 SB 206553 Potent, selective 5-HT2C/5-HT2B antagonist; orally active 10 mg 50 mg

1374 SB 215505 5-HT2B/2C antagonist 10 mg 50 mg

2901 SB 242084 Selective 5-HT2C antagonist; brain penetrant 10 mg 50 mg

5-HT3 Receptors

Agonists 0558 2-Methyl-5-hydroxytryptamine 5-HT3 agonist; also potent 5-HT6 ligand 10 mg 50 mg

Antagonists 1795 Zacopride Highly potent 5-HT3 receptor antagonist; also 5-HT4 agonist 10 mg 50 mg

5-HT4 Receptors

Agonists 4374 BIMU 8 Potent 5-HT4 receptor full agonist 10 mg 50 mg

Antagonists 1322 GR 113808 Potent, selective 5-HT4 antagonist 10 mg 50 mg

1658 GR 125487 Potent, selective 5-HT4 antagonist; active in vivo 10 mg 50 mg

18 | GPCR research Class A: Rhodopsin-like – continued

Category Cat. No. Product Name Description Unit Size

5-ht5 Receptors

Antagonists 3188 SB 699551 Selective 5-ht5a antagonist 10 mg 50 mg

5-HT6 Receptors

Agonists 4337 ST 1936 Selective, high affinity 5-HT6 agonist 10 mg 50 mg

3904 WAY 208466 Selective 5-HT6 agonist 10 mg

Antagonists 1961 SB 258585 Potent, selective 5-HT6 antagonist 10 mg 50 mg

3189 SB 399885 Potent and selective 5-HT6 antagonist 10 mg 50 mg

5-HT7 Receptors

Agonists 1968 AS 19 Potent 5-HT7 agonist 10 mg 50 mg

Antagonists 1612 SB 269970 Potent and selective 5-HT7 antagonist; brain penetrant 10 mg 50 mg 5-HT Receptors (Non-selective) Agonists 3547 Endogenous 5-HT receptor agonist 50 mg

Antagonists 0996 Non-selective 5-HT2 antagonist 50 mg

1064 5-HT1/5-HT2 antagonist 10 mg 50 mg

Class A18

Adenosine A1 Receptors 6 Agonists 1705 2-Chloro-N -cyclopentyladenosine Potent, selective A1 agonist 10 mg 50 mg

3576 (±)-5ʹ-Chloro-5ʹ-deoxy-ENBA Highly selective A1 agonist 10 mg 50 mg

5122 Dansyl-NECA Potent and selective fluorescent A1 agonist 1 mg

Antagonists 0439 DPCPX A1 selective antagonist 100 mg

Adenosine A2A Receptors

Agonists 1063 CGS 21680 A2A agonist 10 mg 50 mg

4334 PSB 0777 Potent adenosine A2A agonist 10 mg 50 mg

Antagonists 5147 Istradefylline Potent and selective adenosine A2A antagonist 10 mg 50 mg

2463 SCH 442416 Very selective, high affinity A2A antagonist 1 mg 10 mg 50 mg

2270 SCH 58261 Potent, highly selective A2A antagonist 10 mg 50 mg

1036 ZM 241385 Potent, highly selective A2A antagonist 10 mg 50 mg

Adenosine A2B Receptors

Agonists 4472 BAY 60-6583 Potent A2B agonist; cardioprotective 10 mg 50 mg

Antagonists 2752 MRS 1754 Selective A2B antagonist 10 mg 50 mg

2009 PSB 1115 Selective human A2B antagonist; water-soluble 10 mg 50 mg

3198 PSB 603 Highly selective A2B antagonist 10 mg 50 mg

tocris.com | 19 CXCR4 – IT1t 4596 H1 – Doxepin 0508

O

NH N S N N N

S

B2-Adrenergic – ICI 118,551 0821 CRF1R – CP-376395 3212

N

O O N Tocris Product Listing Series H

N HO H

Adenosine A2A Receptor in Complex with ZM 241385

Crystal Structure of the Adenosine A2A Receptor in Complex with the A2A Antagonist ZM 241385 A2A – ZM 241385 1036 MGLUR1 – LY 341495 1209 Intracellular Membrane Extracellular

OH NH2 O

O N N N

N N N Cat. No. 1036 H2N H CO2H OH O

• ZM 241385 binds in the A2A binding pocket located close to helices VI and VII, and interacts with the TRP2466.48 residue

• ZM 241385 is a potent and selective A2A receptor antagonistD3 that – Eticloprideexhibits selectivity 1847 for A2A over A1, Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3EML A2B and A3 receptors Jaakola et al (2008) Science 322 1211. PMID 18832607. • The compound is active in vivo

HO O

Category Cat. No. Product Name Description N N Unit Size H

Adenosine A3 Receptors O Cl Agonists 1104 2-Cl-IB-MECA Highly selective A3 agonist 10 mg 50 mg

1579 HEMADO High affinity and selective A3 agonist 10 mg 50 mg

1066 IB-MECA A3 selective agonist 5 mg 25 mg

5428 MRS 5698 High affinity and selective A3 agonist 1 mg Adenosine Receptors (Non-selective) Agonists 3624 Adenosine Endogenous adenosine receptor agonist 50 mg 1691 NECA High affinity adenosine receptor agonist 10 mg 50 mg Antagonists 3200 XAC Adenosine receptor antagonist 10 mg 50 mg Acetylcholine Muscarinic Receptors Agonists 1067 Oxotremorine M Muscarinic receptor agonist 100 mg

3569 Xanomeline Functionally selective M1 agonist 10 mg 50 mg

Antagonists 1105 AF-DX 116 Selective M2 antagonist 10 mg 50 mg

1425 (S)-(+)-Dimethindene M2-selective antagonist 10 mg 50 mg

2507 J 104129 Potent, selective M3 antagonist 10 mg

1671 PD 102807 Selective M4 antagonist 10 mg 50 mg

3727 VU 0255035 Highly selective M1 antagonist 10 mg 50 mg 1414 Non-selective muscarinic antagonist 1 g

Modulators 3634 VU 0238429 Selective positive allosteric modulator of M5 receptors 10 mg 50 mg

3383 VU 152100 Positive allosteric modulator of M4 receptors 10 mg 50 mg

20 | GPCR research

Category Cat. No. Product Name Description Unit Size Other GPCRs GPBA receptors (TGR5) Agonists 4478 GPBAR-A GPBA receptor agonist 10 mg 50 mg 5129 TC-G 1005 Potent and selective GPBA receptor agonist 10 mg 50 mg Neuropeptide FF/AF (NPFF) Receptors

Agonists 3137 Neuropeptide FF Endogenous NPFF1 and NPFF2 agonist 1 mg 5677 RFRP-1 (human) Potent NPFF receptor agonist 1 mg

Antagonists 2707 BIBP 3226 Mixed NPFF and NPY Y1 receptor antagonist 1 mg 10 mg Orphan GPCRs Agonists 4177 AS 1269574 GPR119 receptor agonist 10 mg 50 mg 5666 JNJ 63533054 Potent and selective GPR139 agonist 10 mg 50 mg 1484 Oleylethanolamide Endogenous GPR119 agonist; also GPR55 agonist 10 mg 50 mg 4074 PF9 Potent GPR17 agonist 1 mg 5151 Prosaptide TX14(A) Potent GPR37 and GPR37L1 agonist 1 mg 5355 TC-G 1008 Potent and selective GPR39 agonist 10 mg 50 mg 4255 TC-O 9311 Potent and selective GPR139 agonist 10 mg 50 mg Antagonists 5203 NIBR 189 Potent and selective EBI2 (GPR183) receptor antagonist 10 mg 50 mg Sensory Neuron-specific Receptor Agonists 1763 BAM (8-22) Selective agonist for the sensory-neuron specific 1 mg receptor (SNSR)

DREADD Ligands Designer receptors exclusively activated by designer drugs (DREADDs) are genetically modified GPCRs that are activated by physiologically inert ligands. DREADDs enable the precise experimental manipulation of neuronal signaling, and have multiple non-invasive in vivo applications. Three new DREADD ligands have recently been added to the Tocris range:

Cat. No. Product name Description

4936 N-oxide Activator of muscarinic DREADDs

5548 DREADD agonist 21 NEW Potent muscarinic hM3Dq DREADD agonist

5549 NEW Potent and selective hM3Dq DREADD agonist 5611 Salvinorin B NEW Activates the k-opioid DREADD (KORD)

For more information please visit www.tocris.com/DREADDs

tocris.com | 21 Tocris Product Listing Series Class B: Secretin-like The Secretin-like receptor class consists of receptors for and peptide hormones, including glucagon, secretin and calcitonin receptors. The receptors are key drug targets for the study of many human diseases including, , neurodegeneration,F cardiovascular disease, psychiatric disorders and . F S NH Category Cat. No. Product Name Description Unit Size N Calcitonin and Related Receptors O N O Agonists 3012 α-CGRP (human) OMe CGRP receptor agonist 1 mg O N 1161 CGRP (rat) CGRP receptor agonist; potent vasodilator 100 µg 5031 Synthetic version of (Cat. No. 3418) 500 µg JNJ 27141491 (Cat. No. 5176) NH Antagonists 3419 AC 187 Potent and selective amylin receptor antagonist 500 µg N 4561 BIBN 4096 Potent and selective CGRP receptor antagonist N 10 mg

1169 CGRP 8-37 (rat) CGRP1 receptor antagonist 500 µg N Corticotropin-releasing factor (CRF) Receptors O N Agonists 1151 CRF (human, rat) Stimulates ACTH release 200 µg OMe N NH Antagonists 2778 CRF1 antagonist 10 mg 50 mg Br 2071 Antisauvagine-30 Potent, selective and competitive CRF2 antagonist Purmorphamine (4551) 1 mg 2391 Astressin 2B Selective CRF antagonist 500 µg F 2 2779 CP 154526 Selective, non-peptide CRF1 antagonist 10 mg 50 mg ML 00253764 (4854) 3212 CP 376395 Potent and selective CRF1 antagonist 10 mg 50 mg

2070 K 41498 Highly selective and potent CRF2 antagonist 1 mg F3C 3100 NBI 35965 Potent and selective CRF1 antagonist 10 mg H N N 50 mg N N Gastric Inhibitory Polypeptide (GIP) Receptor N H N O Agonists 2257 GIP (1-39) Highly potent insulinotropic peptide N 1 mg 2084 GIP (human)Cl N Potent insulinotropic gut hormone 1 mg CMPD101 (5642) Glucagon Receptor O O N N N Antagonists 2216 des-His1-[Glu9]-GlucagonH (1-29) H Glucagon receptor antagonist 1 mg S 2311 L-168,049N Potent, human glucagon receptor antagonist; orally active 10 mg H 50 mg Other 2094 Endogenous gut peptide; modulates feeding and metabolism 1 mg TC-G 1008 (5355)

F O NH Potent and Selective CGRP Receptor Antagonist HN O BIBN 4096 N Cat. No. 4561 N H O

HN BIBN 4096 is a potent and selective CGRP receptor antagonist N (IC values are 0.03 and 6.4 nM for human and rat CGRP 50 OH O receptors, respectively). The compound displays high affinity NH 2 for human CGRP receptors (Ki = 14.4 pM), and no significant N affinity for 75 other receptors. MA 2029 (4934) O Br HN HN N N N HO O O

Br

BIBN 4096 (4561)

22 | GPCR research

Category Cat. No. Product Name Description Unit Size Glucagon-like Peptide Receptors Agonists 1933 Exendin-4 Potent GLP-1 receptor agonist 1 mg 5374 GLP-1 (7-37) Endogenous bioactive GLP-1 receptor ligand 1 mg 2258 GLP-2 (human) Endogenous hormone; displays intestinotrophic activity 1 mg 2259 GLP-2 (rat) Endogenous hormone; displays intestinotrophic activity 1 mg 2082 Glucagon-like peptide 1 (7-36) Potent insulinotropic peptide 1 mg (human, rat) Antagonists 2081 Exendin-3 (9-39) Potent GLP-1 receptor antagonist 1 mg 3266 GLP-1 (9-36) Metabolite of GLP-1-(7-36) (Cat. No. 2082) 1 mg Modulators 4778 BETP Positive allosteric modulator of GLP-1 receptors 10 mg 50 mg PACAP Receptors Agonists 1183 PACAP 1-27 Potent stimulator of adenylyl cyclase 100 µg 1186 PACAP 1-38 Potent stimulator of adenylyl cyclase 100 µg

Antagonists 3236 PACAP 6-38 Potent PAC1 receptor antagonist 100 µg Parathyroid Hormone (PTH) Receptors Agonists 5487 DPC AJ1951 Potent PTH receptor agonist 1 mg 3011 Parathyroid hormone4596 (1-34) PTH receptor agonist H1 – Doxepin 0508 1 mg CX(human)CR4 – IT1t Secretin Receptor Agonists 1918 Secretin (human) Gastrointestinal peptide 1 mg 1919 Secretin (rat) Gastrointestinal peptide 1 mg VIP Receptors O Agonists 2711 Bay 55-9837 Potent and selective VPAC2 agonist 1 mg NH N 1911 VIP (human, rat, mouse, rabbit, Endogenous VIP receptor agonist 1 mg canine, porcine)S N N N Antagonists 3054 [D-p-Cl-Phe6,Leu17]-VIP Selective VIP receptor antagonist 1 mg 1905 VIP (6-28)S (human, rat, porcine, VIP receptor antagonist 1 mg bovine)

CRF1 Receptor in Complex with CP 376395

Crystal StructureB2-Adrene of therg icCRF – ICI1 Receptor 118,551 in Complex0821 with the CRF1 Antagonist CP 376395 CRF1R – CP-376395 3212 Intracellular Membrane Extracellular

N Cat. No. 3212 O O N H

N • CP 376395 binds to a hydrophobic pocket, defined HO H by residues of TM3, TM5 and TM6, located in the cytoplasmic domain of the receptor • CP 376395 is a non-peptide high affinity and selective

CRF1 antagonist (Ki values are 12 and >10,000 nM for CRF1 and CRF2 receptors, respectively) Image adaptedA2A from – the ZM RSCB 241385 PDB (www.rcsb.org)1036 of PDB ID: 4K5Y • The compound attenuates CRF-induced HPA axis Hollenstein et al (2013) Nature 499 438. PMID 23863939. activation inMG vivoLUR1 – LY 341495 1209

OH NH2 O

O N N N

N N N H2N H CO2H OH O tocris.com | 23

D3 – Eticlopride 1847

HO O

N N H O Cl Tocris Product Listing Series Class C: Glutamate The Glutamate receptor class of GPCRs consists of receptors that have amino acids, ions and sugars as their endogenous ligands, including glutamate, GABA and calcium. Class C receptors are highly susceptible to modulation by ligands that bind to allosteric binding sites, particularly metabotropic glutamate receptors.

Category Cat. No. Product Name Description Unit Size Calcium-sensing Receptor Agonists 4749 Strontium chloride Calcium sensing receptor (CaSR) agonist 50 mg Antagonists 3626 NPS 2143 Selective antagonist of the calcium-sensing receptor; 10 mg orally active calcilytic agent 50 mg Modulators 4387 Calhex 231 Negative allosteric modulator of the calcium-sensing 10 mg receptor 50 mg 3815 R 568 Positive allosteric modulator of the human calcium-sensing receptor 10 mg 50 mg

GABAB Receptor

Agonists 0796 (R)- Selective GABAB agonist; active enantiomer of (RS)-Baclofen 10 mg (Cat. No. 0417) 50 mg 3400 RuBi-GABA Caged GABA; excitable by visible wavelength 10 mg

Antagonists 1245 CGP 35348 Brain penetrant, selective GABAB antagonist 10 mg 50 mg

1246 CGP 52432 Potent, selective GABAB antagonist 10 mg 50 mg

1088 CGP 54626 Potent, selective GABAB antagonist 10 mg 50 mg

1248 CGP 55845 Potent, selective GABAB antagonist 10 mg 50 mg

0984 SCH 50911 Selective, competitive, orally active GABAB antagonist 10 mg 50 mg

Modulators 1513 CGP 7930 Positive modulator at GABAB receptors 10 mg 50 mg Glutamate (Metabotropic) Group I Receptors Agonists 0187 (±)-trans-ACPD Group I/group II mGlu agonist 10 mg 50 mg

1049 CHPG mGlu5 selective agonist 10 mg 50 mg

3695 CHPG Sodium salt Selective mGlu5 agonist; sodium salt of CHPG 10 mg (Cat. No. 1049) 50 mg 0342 (RS)-3,5-DHPG Selective group I mGlu agonist 1 mg 10 mg 50 mg 0805 (S)-3,5-DHPG Selective group I mGlu agonist; active enantiomer of 5 mg 3,5-DHPG (Cat. No. 0342) 10 mg 0188 L-Quisqualic acid Group I mGlu agonist; also AMPA receptor agonist 1 mg 10 mg 50 mg

Antagonists 5614 AZD 2066 mGlu5 antagonist; orally bioavailable and brain penetrant 10 mg

2501 Bay 36-7620 Non-competitive mGlu1 antagonist with inverse agonist 10 mg activity 0323 (S)-4-Carboxyphenylglycine Competitive group I mGlu antagonist/weak group II agonist 10 mg 50 mg

1028 CPCCOEt Selective non-competitive mGlu1 receptor antagonist 10 mg 50 mg

2333 JNJ 16259685 Highly potent, mGlu1-selective non-competitive 10 mg antagonist 50 mg

1237 LY 367385 Selective mGlu1a antagonist 10 mg 50 mg

24 | GPCR research

Category Cat. No. Product Name Description Unit Size 3696 (RS)-MCPG disodium salt Sodium salt of (RS)-MCPG (Cat. No. 0336) 10 mg 50 mg

1212 MPEP mGlu5 antagonist and positive allosteric modulator 10 mg at mGlu4 50 mg

2921 MTEP Potent, selective mGlu5 antagonist 10 mg 50 mg

Modulators 3235 CDPPB Positive allosteric modulator at mGlu5 10 mg 50 mg 5275 LSN 2463359 Potent and selective positive allosteric modulator 10 mg

at mGlu5 50 mg 5322 VU 0409106 Potent and selective negative allosteric modulator 10 mg

at mGlu5 50 mg

5377 VU 0483605 Positive allosteric modulator at mGlu1 10 mg 50 mg Glutamate (Metabotropic) Group II Receptors Agonists 0975 DCG IV Very potent, selective group II mGlu agonist; also NMDA 1 mg agonist 10 mg 50 mg 3246 LY 354740 Potent and highly selective group II mGlu agonist 10 mg 50 mg 2453 LY 379268 Highly selective group II mGlu agonist 10 mg 50 mg 5064 LY 379268 disodium salt Selective group II mGlu receptor agonist; sodium salt of 10 mg LY 379268 (Cat. No. 2453) 50 mg Antagonists 1209 LY 341495 Highly potent, selective group II antagonist 1 mg 10 mg 50 mg 4062 LY 341495 disodium salt Disodium salt of LY 341495 (Cat. No. 1209) 1 mg 10 mg 50 mg 0337 (S)-MCPG Non-selective mGlu antagonist; active isomer of (RS)-MCPG 10 mg (Cat. No. 0336) 50 mg

Modulators 3283 LY 487379 Positive allosteric modulator selective for mGlu2 10 mg 50 mg

Glutamate (Metabotropic) Receptor Allosteric Modulators

Cl O Cl O N

Me N N NH Cl O

MPEP (1212) F3C VU 0483605 (5377) mGlu antagonist and positive allosteric 5 N Positive allosteric modulator at mGlu1 O S O modulator at mGlu4 OMe N N

N O O H N N LY 487379 (3283) N CN

H Positive allosteric modulator selective for mGlu2 O N N F O S

VU 0409106 (5322) CDPPB (3235)

Potent and selective negative allosteric Positive allosteric modulator at mGlu5

modulator at mGlu5

tocris.com | 25

Glutamate (Metabotropic) Receptors CXCR4 – IT1t 4596 H1 – Doxepin 0508

O

NH N S Tocris Product ListingN SeriesN N

S

Category Cat. No. Product Name Description Unit Size Glutamate (Metabotropic)B2-Adrene Grouprgic III – ReceptorsICI 118,551 0821 CRF1R – CP-376395 3212 Agonists 2385 AMN 082 The first selective mGlu7 agonist 10 mg 50 mg 0103 L-AP4 Selective group III mGlu agonist 1 mg 10 mg N 50 mg

Antagonists 0972 CPPGO Very potent group III mGlu Oantagonist N 10 mg H 50 mg

2963 MMPIP Potent, allosteric mGlu7-selective antagonist 1 mg N HO H 10 mg 50 mg

mGlu1 Receptor in Complex with LY 341495 CrystalA2A Structure – ZM 241385 of the mGlu1036 Receptor in Complex with the Group II mGlu Receptor Antagonist LY 341495 1 MGLUR1 – LY 341495 1209

OH NH2 O

O N N N

N N N H2N H Cat. No. 1209 CO2H OH O

• Data regarding the binding of LY 341495 to mGlu1 have yet to be published D3 – Eticlopride 1847 • LY 341495 is a potent and selective group II mGlu receptor antagonist (IC50 values are 1.3 and 2.3 nM for mGlu3 and mGlu2 receptors, respectively) that exhibits Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3KS9 selectivity over group I and III mGlu receptors Dobrovetsky et al (2009)H DataO yet to be published. • The compound is brain penetrant and active in vivo O

N N H O Cl

26 | GPCR research GPCR Allostery GPCR allostery refers to the binding of ligands at sites on the receptor distinct from the orthosteric binding site, termed allosteric binding sites. Allosteric ligands can have intrinsic agonist/inverse agonist activity of their own, potentiate/decrease the effects of orthosteric ligands, or be neutral ligands with no intrinsic/modulatory activity.

Allosteric Modulation: Key Characteristics of GPCR Allostery: Allosteric modulators are ligands that bind to Enhanced Selectivity: receptor allosteric binding sites and influence the Allosteric binding sites have greater sequence divergence than the binding affinity and/or the signaling efficacy of the often conserved orthosteric site between receptor subtypes. Therefore orthosteric ligand. allosteric ligands have the potential to offer greater subtype selectivity for receptors, such as the acetylcholine musarinic receptor. Those that potentiate the action of an orthosteric ligand are termed positive allosteric modulators The Saturation Effect: (PAMs), whereas those that decrease the action are The effect of an allosteric ligand reaches a saturation point over a certain termed negative allosteric modulators (NAMs). concentration, whereby no further pharmacological effects are observed. This enables greater fine-tuning of physiological responses, and lowers Unlike some allosteric ligands that have intrinsic the risk of target-based overdose. agonist activity, allosteric modulators only have an effect in the presence of an orthosteric ligand (a Probe Dependence: ligand that binds to the binding site of the receptors The effect of an allosteric modulator can be dependent on the orthosteric

endogenous ligand). They therefore have the ligand. For example the allosteric modulator advantage of being able to selectively influence PD 81723 (Cat. No. 1363) enhances the affinity of the agonist [3H]CHA, 3 physiological processes in tissues where the but not the antagonist [ H]CPX, for the A1 receptor. endogenous ligand is present. Biased Signaling: Allosteric modulators have been developed for Biased agonism/modulation refers to the ability of allosteric (and Class A, B and C GPCRs. They are especially useful orthosteric) ligands to preferentialy induce certain intracellular signaling for Class B GPCRs, which have orthosteric binding pathways at the exclusion of others. Allosteric modulators can also sites that are difficult to target pharmacologically. impose bias signaling on certain orthosteric agonists. See pg 30 for more information. For references and further reading please see pg 31

Orthosteric Signaling Positive Allosteric Modulation Negative Allosteric Modulation Neutral Allosteric Ligand

Orthosteric PAM NAM Neutral allosteric agonist ligand

G protein

Signaling Potentiated signaling Reduced signaling Unaltered signaling

Allosteric Modulation Schematic Schematic representing orthosteric and allosteric GPCR signaling. Positive allosteric modulators (PAMs) potentiate the binding affinity (dark green pointed arrow) and/or signaling efficacy (light red pointed arrow) of the orthosteric ligand, whereas negative allosteric modulators (NAMs) decrease the binding affinity (dark green flat arrow) and/or the signaling efficacy (light red flat arrow) of the orthosteric ligand. Neutral allosteric ligands have no intrinsic activity and have no effect on orthosteric signaling, although they are able to block the binding of other allosteric ligands to the allosteric binding site that they occupy. Allosteric modulators exert their effects on orthosteric ligand-induced signaling by stabilizing the receptor in a conformation that is either favorable (PAMs) or unfavorable (NAMs) towards the ligands binding affinity and/or signaling efficacy. Figure adapted from Wootenet al (2013) Nat.Rev.Drug Discov. 12 630.

tocris.com | 27 Tocris Product Listing Series Class F: Frizzled The Frizzled receptor class of GPCRs consists of frizzled (FZD) receptors, FZD1-8 and the smoothened receptor (SMOH), and taste receptors. FZD1-8 are activated by Wnt proteins, whereas SMOH is activated by Hedgehog (Hh) signaling. The SMOH receptor is unique in that it does not directly interact with its endogenous ligand.

Category Cat. No. Product Name Description Unit Size Smoothened Receptor Agonists 4551 Purmorphamine Smo receptor agonist 10 mg 50 mg 4366 SAG Potent Smoothened receptor agonist; activates the 1 mg Hedgehog signaling pathway Antagonists 1623 Cyclopamine Inhibitor of Hedgehog (Hh) signaling; antagonizes 1 mg smoothened activity 5554 IHR 1 Potent Smo antagonist 10 mg 50 mg 1974 SANT-1 Inhibitor of hedgehog (Hh) signaling; antagonizes 10 mg smoothened activity 50 mg F F S NH Smoothened Receptor Agonist N O N Purmorphamine Cat. No. 4551 O OMe O N

Purmorphamine is a smoothened receptor agonist that induces JNJ 27141491 (Cat. No. 5176) NH osteogenesis in mouse mesenchymal progenitor cells. The N N compound also transdifferentiates pre-adipocytes and myoblasts into in combination with BMP-4. O N N

OMe N NH

Br Purmorphamine (4551) F

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and into the commercial arena. We workF in3C partnership with many scientists within both Universities and pharmaceutical companies to bring life scienceH tools to the global research community. N N N N N H The Tocris policy has always been to Onever knowingly infringe third party intellectual property. It is our N N intention to remain a responsible and ethical supplier, and work with the scientific community. Cl N CMPD101 (5642)

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BIBN 4096 (4561) GPCR research GPCR Signaling GPCRs mediate signal transduction from the cytosol to the cell interior. Agonist binding to GPCRs results in the coupling of heterotrimeric G proteins, which are subsequently released by GDP/GTP exchange. The G protein subunits activate effector proteins, such as cyclases and phospholipases to induce intracellular signaling cascades.

Category Cat. No. Product Name Description Unit Size Adenylyl Cyclase Activators 1099 Forskolin Adenylyl cyclase activator 10 mg 50 mg 1603 NKH 477 Water-soluble adenylyl cyclase activator 10 mg 50 mg Inhibitors 1435 SQ 22536 Adenylyl cyclase inhibitor 10 mg 50 mg cAMP Other 5255 6-Bnz-cAMP sodium salt Cell permeable cAMP analog 1 mg 1140 8-Bromo-cAMP, sodium salt Cell-permeable cAMP analog 10 mg 50 mg 1337 cAMPS-Rp cAMP antagonist 1 mg 1333 cAMPS-Sp Cell-permeable cAMP analog 1 mg 1141 Dibutyryl-cAMP, sodium salt Cell-permeable cAMP analog 10 mg 50 mg G Protein (Heterotrimeric) Inhibitors 4567 CCG 50014 Potent and selective inhibitor of regulator of G-protein 10 mg signaling 4 (RGS4) protein 50 mg 4773 ESI 09 EPAC inhibitor 10 mg 50 mg 3090 Gallein Inhibitor of βγ signaling 50 mg

Other 3097 Pertussis Toxin Catalyzes ADP-ribosylation of Gi, Go and Gt 50 µg GRK Inhibitors 5642 CMPD101 Potent and selective GRK2/3 inhibitor 10 mg 3594 GRK2i GRK2 inhibitory polypeptide; Gβγ antagonist 1 mg

IP3 Receptor

Antagonists 1224 2-APB IP3 receptor antagonist; also TRP channel modulator 10 mg 50 mg 2+ Other 1280 (-)-Xestospongin C Reported inhibitor of IP3-dependent Ca release 10 µg Phospholipases Inhibitors 1437 D609 Selective PC-PLC inhibitor 10 mg 50 mg 3022 Edelfosine Selective PI-PLC inhibitor; also PAF receptor agonist 10 mg 3600 FIPI Phospholipase D inhibitor 10 mg 50 mg 1268 U 73122 inhibitor 10 mg 50 mg 4133 U 73343 Analog of U 73122 (Cat. No. 1268) 10 mg 50 mg 3575 VU 0155069 Potent and selective PLD1 inhibitor 10 mg 50 mg 4171 VU 0364739 Potent and selective PLD2 inhibitor 10 mg 50 mg 2522 YM 26734 Secretory phospholipase A2 (sPLA2) inhibitor 10 mg

tocris.com | 29 Tocris Product Listing Series Bias Signaling Biased agonism or functional selectivity is the phenomenon whereby ligands can selectively activate certain signaling pathways, while others remain inactive. Biased ligands can stabilize their GPCR in different active conformations, resulting in bias towards certain pathways such as G protein- or β-arrestin-dependent signaling.

G Protein-dependent Signaling β-Arrestin-dependent Signaling

G Gαq α P Gαi β-arrestin P Gαs

GRK5/6 AC PLC Raf ASK1 GRK5/6

β-arrestin cAMP ATP IP3 DAG MEK1 MEK4 PI 3-K RhoA c-Src

PKA EPAC Ca2+ PKC ERK JNK Akt ROCK

Activation Movement Inhibition Blocked effect

Biased Signaling Schematic Schematic representing biased signaling towards G protein- and β-arrestin signaling. GPCR signaling classically results in the downstream activation of G proteins, which stimulate intracellular effectors such as AC and PLC. Activated GPCRs are phosphorylated by GRKs, recruiting β-arrestin to the receptor and stimulating further signaling pathways such as MAPK, PI 3-K, RhoA and c-Src signaling. Ligands have recently been developed that can selectively activate G protein- or β-arrestin-dependent signaling, while having no significant effect on the other pathway. Certain ligands can also stimulate specific Gα proteins over others. This phenomenon was termed biased agonism. These biased ligands can induce GPCRs to adopt certain active conformations that preferentially activate different intracellular signaling pathways. Abbreviations: AC, adenylyl cyclase; Akt, B; cAMP, cyclic adenosine monophosphate; ASK1, signal-regulating kinase 1; ATP, ; DAG, diacylglycerol; EPAC, exchange factor directly activated by cAMP 1; ERK, extracellular signal–regulated kinase; GRK, G protein-coupled receptor kinase; IP3, ; JNK, c-Jun N-terminal kinase; MEK, mitogen- activated protein kinase kinase; PI 3-K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKA, ; PKC, protein kinase C; PLC, phospholipase C; RhoA, Ras homolog gene family, member A; ROCK, Rho-associated protein kinase.

Allosteric Modulation and Bias Signaling: As well as many orthosteric ligands being identified as bias agonists, allosteric ligands have also been shown to exhibit signal bias (for an overview of allosteric modulation see pg 27). Certain allosteric modulators have the ability to direct orthosteric agonist signaling towards specific signaling pathways. For example ORG 27569 (Cat. No. 2957) acts as a negative allosteric modulator (NAM) of

orthosteric agonist-mediated CB1 Gαs signaling and a positive allosteric modulator (PAM) on β-arrestin signaling, while Gadolinium

(Cat. No. 4741) is a PAM of agonist-mediated mGlu1α Gαq signaling and a NAM on Gαs signaling. The discovery of allosteric ligands that can direct orthosteric ligand signal bias offers the potential for the augmentation of desirable physiological signaling pathways to produce more effective therapeutic drugs.

30 | GPCR research

Bias Signaling (cont.): Therapeutic Applications: Biased agonism is of great interest therapeutically as it offers the potential to preferentially activate signaling pathways that induce the desired physiological effect, while having no effect on those that cause adverse side effects. Biased agonists have the potential to revolutionize the drug discovery process, through the generation of safer and more effective drugs.

Analgesia: • β-arrestin biased D2 agonists have been recently developed that • Morphine (Cat. No. 5158), an opioid receptor agonist, is exhibit antipsychotic activity in mice without the motor side effects commonly used clinically to relieve pain Cardiovascular Disease: • β-arrestin knock-out mice administered morphine experience enhanced analgesia and fewer side effects, such as respiratory • Angiotensin II receptor type 1 (AT1) antagonists have long been and gastrointestinal dysfunction used in the treatment of , however reduced cardiac output is a side effect • The development of opioid receptor bias agonists that selectively activate G protein signaling may result in improved analgesic • The β-arrestin biased AT1 antagonist TRV027 has been shown to drugs without the adverse side effects reduce blood pressure and enhance cardiac performance in rats

• Furthermore β-arrestin biased AT1 agonists have been found to : protect against cell death during cardiac injury, which could be

• Dopamine D2 receptor antagonists are clinically used as applied to the treatment of cardiac ischemia antipsychotics, but are associated with motor side effects such as catalepsy and dyskinesias

References and Further Reading

GPCR Crystal Structures: Bortolato et al (2014) Structure of Class B GPCRs: new horizons for drug discovery. Br.J.Pharmacol. 171 3132 Granier and Kobilka (2012) A new era of GPCR structural and chemical biology. Nat.Chem.Biol. 8 670 Stevens et al (2013) The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat.Rev.Drug Discov. 12 25 Tautermann (2014) GPCR structures in drug design, emerging opportunities with new structures. Bioorg.Med.Chem.Lett. 24 4073 GPCR Allostery: Christopoulos (2014) Advances in G protein-coupled receptor allostery: from function to structure. Mol.Pharmacol. 86 463 Christopoulos et al (2014) International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol.Rev. 66 918 Kollias-Baker et al (1994) Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine. Circ.Res. 75 961 Müller et al (2012) Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development. Pharmacol.Ther.135 292 Wooten et al (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat.Rev.Drug Discov. 12 630 Bias Signaling: Kenakin and Christopoulos (2013) Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat.Rev.Drug Discov. 12 205 Khoury et al (2014) Allosteric and biased G protein-coupled receptor signaling regulation: potentials for new therapeutics. Front.Endocrinol. 5 1 Rankovic et al (2014) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg.Med.Chem.Lett. 26 241 Sonoda et al (2014) β-Arrestin-1 mediates glucagon-like peptide-1 signaling to secretion in cultured pancreatic beta cells. Proc.Natl.Acad.Sci.U.S.A. 105 6614

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