TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference
Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994
Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998
Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993
Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001
Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine,
Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002
Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999
Human α2D-adrenergic Prazosin McCune et al., 2000
Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000
Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine
Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101
Hamster α1B-adrenergic (CAM) Prazosin, WB 4101, phentolamine, REC15/3039, Rossier et al., 1999; Hein et REC15/2739, REC15/2869, REC15/3011, 5- al., 2001 methylurapidil, BMY 7378, WAY 100,635, S(+)- niguldipine, SNAP 5089, BE 2254, tamsulosin, RS- 17053, terazosin, (+)-cyclazosin, (–)-cyclazocine, REC15/2615, alfuzosin, indoramin, corynthanine, spiperone, AH11110A, doxazosin, SB 216,469 Rat α1d-adrenergic WB 4101 BMY 7378, phentolamine, chloroethylclonidine, 5- Garcia-Sainz and Torres- methyl-urapidil Padilla, 1999
Human α1A-adrenergic (CAM) REC15/3039, 5-methylurapidil, WAY 100,635, WB 4101, Rossier et al., 1999; Zhu et al., REC15/2739, S(+)niguldipine, SNAP 5089, phentolamine, BE2254, 2000 REC15/2869, tamsulosin, RS-17053, prazosin, terazosin, (+)cyclazosin, REC15/3011, KMD- (–)-cyclazocine, REC15/2615, alfuzosin indoramin 3213 corynthanin, spiperone, AH11110A, BMY 7378
Human α1B-adrenergic (CAM) Prazosin, WB 4101, phentolamine Cotecchia et al., 1995
Human histamine H1 Cetirizine, loratridine, epinastine, acrivastine, Bakker et al., 2000, 2001 mepyramine, KW 4679
Histamine H2 Burimamide Cimetidine, ranitidine Smit et al., 1996
Histamine H2 Tioditine Monczor et al., 1998
Human histamine H3 VUF4904 Iodophenpropit, thioperamide, clopenpropit, VUF4903, Morisset et al., 2000; Wieland VUF5202, ciproxifan, GT2394, JB98064 et al., 2001; Wulff et al., 2002
Rat histamine H3 Iodophenpropit, thioperamide, clopenpropit, ciproxifan Wulff et al., 2002 Human bradykinin B2 FR 173657 Drube and Liebmann, 2000 Rat bradykinin B2 HOE140, NPC17731, NPC567 Leeb-Lundberg et al., 1994
Rat 5-HT2C Spiroxatrine, BOL Spiperone ketanserin, clozapine, methysergide, Barker et al., 1994; Westphal metergoline, mesulergine, ritanersin, mianserin, and Sanders-Bush, 1994; cyproheptadine, deramciclane Labrecque et al., 1995; Hartman and Northup, 1996; Palvimaki et al., 1998
Human 5-HT1A p-MPPF, WAY 100,135 Spiperone, p-MPPI, WAY 100,635, methiothepin Barr and Manning, 1997; Newman-Tancredi et al., 1997a,b; Stanton and Beer, 1997; Cosi and Koek, 2000 322 Rat 5-HT2A Cys Lys Chlorpromazine, clozapine, haloperidol, loxapine, Egan et al., 1998a,b risperidone, spiperone, ketanserin 312 Rat 5-HT2C Ser Klys Haloperidol, Mianserin, mesulergine, methysergide, clozapine, Herrick-Davis et al., 1997, chlorpromazine, olanzapine, ziprasidone, risperidone, cyproheptadine, 1998, 2000 perphenazine ketanserin Human 5-HT1B SB 18127 SB 224289, SB 236057, methiothepin, olanzapine, Gaster et al., 1998; Cayla et clozapine, risperidone, ocaperidone, S16924, ORG-5222, al., 1999; Millan et al., 1999; ziprasidone Newman-Tancredi et al., 2000; Audinot et al., 2001
Guinea Pig 5-HT1B SB 224289, methiothepin, ritanserin Pauwels et al., 1998
Human 5-HT1B (CAM) GR 55562, methiothepin, ritanserin Pauwels, 1997; Pauwels et al., 1999
Human 5-HT1C SB 228357, SB 243213 Bromidge et al., 2000a,b
Human 5-HT1D SB 18127 Ketanserin, methiothepin, ocaperidone, SB 224289, Pauwels, 1997; Pauwels et al., ritanserin, olanzapine, clozapine, risperidone, 1997; Brys et al., 2000; ocaperidone, S16924, ORG-5222, ziprasidone, Audinot et al., 2000, 2001 haloperidol, chlorpromazine
Human 5-HT2C-INI Thioridazine, Sertindole, zotepine, ziprasidone, tiospirone, olanzapine, Herrick-Davis et al., 2000 mesoridazine clozapine, risperidone, fluperlapine, tenilapine, loxapine trifluoperazine, fluphenazine, spiperone, haloperidol, pimozide, thiothixene, chlorpromazine, perphenazine
Murine 5-HT4(a) RS100235 SB 207266, GR 125487 Claeysen et al., 2000
Human 5-HT4C ML10375 Blondel et al., 1998
Human 5-HT7 long Risperidone, methiothepin, mesulergine, clozapine, Thomas et al., 1998; Audinot olanzapine, ketanserin, SB 258719 et al., 2001
Rat dopamine D1A Sch23390; (–)- (+)-Butaclamol, chlorpromazine, clozapine, Cai et al., 1999 Butaclamol fluphenazine, cis-flupenthixol, haloperidol
Human dopamine D3 Nafatotride Haloperidol, (+)-UH-232, (+)-AJ-76, raclopride, Griffon et al. 1996; Malmberg clozapine, fluphenazine, thioperazine, eticlopride, et al., 1998 prochlorperazine, risperidone, flupenthixol, pimozide, chlorpromazine, sulpiride
Human dopamine D2 Haloperidol, flupenthixol Nilsson et al., 1996 Murine µ-opioid β-Flunaltrexamine Liu et al., 2001 Murine δ-opioid TIPP[ψ], TIPP, ICI 174864, RTI-5989, RTI-5989-23, RTI-5989-25 Costa and Herz, 1989; naloxone, MR2266, Mullaney et al., 1996; naltriben Szekeres and Traynor, 1997; benzylidenenaltrexone Zaki et al., 2001
Human δ-opioid H-Dmt-Tic-NH2, H-Dmt-Tic-OH, N,N(CH3)2Dmt-Tic-NH2, Tic-OH, HS Hoshohata et al., 1999; naltrindole, TIPP 378, (2S,3R)TMT-L-Tic-OH, ICI 174864, TICP(ψ) LaBarre et al., 2000 Rat µ-opioid D3,49(164) mutant Diprenorphine Naloxone, naltrexone, naloxone methiodide Li et al., 2001
Bovine adenosine A1 0861, WRC-0342 XAC, CPX, WRC-0571 Freissmuth et al., 1991
Human adenosine A1 N-0861, N-0840, WRC- CPX, XAC, CGS-15943, WRC-0571 Shryock et al., 1998 0342 NPY-1 BIBP3226 Vanderheyden et al., 1997 Human neurotensin 2 Neurotensin Levobastine, JMV431, JMV457, JMV509, JMV2004 Richard et al., 2001 Human calcitonin type 2 AC512, AC66, AC423 Chen et al., 1997, 1999a,b
Rat calcitonin C1b AC512, SDZ-212-769, sCT-(8-32), SDZ-219-379 Pozvek et al., 1997 11 12 Human PTH (CAM) [Leu ,D-Trp ]hPTHrP(7-37)NH2T,; [D- Gardella et al., 1996 12 34 Trp ,Tyr ]bPTHrP(7-37)NH2T Kaposi’s sarcoma-associated IP-10 Geras-Raaka et al., 1998 Herpesvirus GPCR CCK L-740,093R Beinborn et al., 1998 Melanocortin-4 SHU9119 AgRP(83-132) Nijenhuis et al., 2001
Rat CB1 SR 141716A, CP-272871 Meschler et al., 2000 Human Melatonin 1A Luzindole Roka et al., 1999
Human CB1 SR 141716A, AM630 Landsman et al., 1998; MacLennan et al., 1998; Shire et al., 1999
Human CB2 SR 144528, AM630, cannabinol MacLennan et al., 1998; Bouaboula et al., 1999; Portier et al., 1999; Ross et al., 1999; Shire et al., 1999 Human TRH (CAM) Chlorodiazepoxide Grimberg et al., 1999 ORF-74 IP-10, SDF-1α, Met-SDF-1α, vMIP-II Rosenkilde et al., 1999
Vasopressin V2 (CAM) SR-121463A, OPC-31260 Morin et al., 1998 Porcine ADH Chlorpropamide Durr et al., 2000 Human PAF (CAM L231R) WEB2086, alprazolam, CV3988, BN52021 Dupré et al., 2001 GLP-1 Exendin-(9-39) Serre et al., 1998
Human MT1 melatonin N-[(1-H-Indol-2- N-[(1-H-Indol-2-yl) alkyl]acylamino deriv.5b,c,k Spadoni et al., 1998 yl)alkyl]acylamino deriv.8-11 Human metabotropic glutamate MPEP, BAY36-7620 Pagano et al., 2000; Carroll et receptor al., 2001 Human muscarinic m1 Atropine, pirenzepine, NMS, QNB, trihexylphenidyl, 4- Burstein et al., 1997 diphenylacetoxy-N-methylperidine Human muscarinic m3 Atropine, pirenzepine, NMS, QNB, trihexylphenidyl, 4- Burstein et al., 1997 diphenylacetoxy-N-methylperidine Human muscarinic m5 Atropine, pirenzepine, NMS, QNB, trihexylphenidyl, 4- Burstein et al., 1997 diphenylacetoxy-N-methylperidine Human muscarinic m2 Atropine, N-methylscopolamine, QNB, AF-DX 116 Jakubic et al., 1995 Human muscarinic m4 Atropine, N-methylscopolamine, QNB, AF-DX 116 Jakubic et al., 1995 Rat muscarinic Atropine, N-methylscopolamine, QNB, AF-DX 116 Jakubic et al., 1995 Human formyl peptide receptor N-t-butoxycarbonyl-[L- Cyclosporin Wenzel-Seifert et al., 1998 leucyl-phenala]2 (+)-AJ-76, (+)-(1S,2R)-5-methoxy-1-methyl-2-(propylamino)tetralin (+)-UH-232, (+)-(1S,2R)-5-methoxy-1-methyl-2-(dipropylamino)tetralin) (2S,3R)TMT-L-Tic-OH, β-methyl-2′,6′-dimethyltyrosine-L-tetrahydroquinoline-3-carboxylic acid AF-DX 116, 11-[[2-[(diethyl-amino)-methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one AgRP(83-132), Agouti-related protein (83-132) AH11110A, 1-(2-biphenyloxy)-4-imino-4-(1-piperidinyl)-2-butanol AM630, 6-iodopravadoline BAY36-7620, [(3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on BE 2254, (2[-(4-hydroxyphenyl)-ethyl-aminomethyl]tetralone HCl BIBP3226, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-arginine amide BMY 7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride BN52021, Ginkgolide B CGP20712A, [2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2- propanolmethanesulfonate CP-272871, 1-(2-chlorophenyl)-4-cyano-5-(4-methyoxyphenyl)-1H-pyrazole-3-carboxylic acid phenylamide CPX, 8-cyclopentyl-1,3-dipropylxanthine FR 173657, ((E)-3-(6-acetamido-3-pyridyl)-N-[N-2-4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl]phenyl]-N-methylaminocarbonyl- methyl]acrylamide) GR 125487, ([1-[2(methylsulfonyl-amino)ethyl]4-piperidinyl]methyl-5-fluoro-2-methoxy-1-H-indole-3-carboxylate, hydrochloride) GT2394, (1R*,2R*)-trans-2-imidazol-4-ylcyclopropyl) (cyclohexylmethoxy) carboxamide 0 3 6 7 8 HOE140, (D-Arg [Hyp -Thi -D-Tic -Oic ])bradykinin ICI 118,551, erythro-DL-1-(7-methylindan-4,1-oxy)-3-isopropylaminobutan-2-ol ICI 174864, [N,N-diallyl-Tyr1,Aib2,3,Leu5]enkephalin IP-10, (human) interferon inducible protein 10 JB98064, N-(4-chlorobenzyl)-N-(7-pyrrolodin-1-ylheptyl)guanidine JMV2004, H-Lys-Lys-Pro-(CH2-NH)-D-Trp-Ile-Leu-OH JMV431, Boc-Arg-Arg-Pro-Tyr-(CH2-NH)-Ile-Leu-OH JMV457, Boc-Arg-Arg-Pro-D-Trp-Ile-Leu-OH JMV509, Boc-Lys-Lys-Pro-D-Nal-Ile-Leu-OH KMD-3213, (–)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide KW 4679, olopatadine hydrochloride MIP, macrophage inflammatory protein MK912, 2s,12bs-1′,3′dimethyspiro(1,3,4,5′,6,6′,7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinazoline)-2,4′-pyrimidin-2′one ML10375, 2-(cis-3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate MPEP, 2-methyl-6-(phenylethynyl)pyridine MPV-2088, [(4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole]HCl MR2266, (–)-5,9-diethyl-2-(3-furylmethyl)-2′-hydroxy-6,7-benzomorphan N-0840, N6-cyclopentyl-9-methyladenine N-0861, (±)-N6-endonorbornan-2-yl-9-methyladenine NMS, N-methyl-scopolamine NPY-1, neuropeptide Y-1 OPC-31260, 5-dimethylamino-1-{4-(2-methylbenzoylamino)-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine ORF-74, KSHV G protein-coupled receptor ORG-5222, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H dibenz[2,3:6,7]oxepino[4,5-c]pyrrole p-MPPF, 4-(2-methoxyphenyl)-1-[2-(n-2[dprime]-pyridinyl)-p-fluorobenzamido]ethyl-piperazine p-MPPI, 4-(2-methoxyphenyl)-1-[2-(n-2[dprime]-pyridinyl)-p-iodobenzamido]ethyl-piperazine PTH, parathyroid hormone QNB, quinuclidinyl benzilate REC15/3039, 8-[2-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl-ethyl]-8-azaspiro[4,5]decane-7,9-dione RS-17053, N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine RTI-5989, (+)-N-(trans-4′-phenyl-2′-butenyl)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine fumarate RTI-5989-23, (+)-N-[trans-4′-(2-methylphenyl)-2′-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine fumarate RTI-5989-25, (+)-N-[trans-4′-(2-chlorophenyl)-2′-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine fumarate RX 811059, 2-(2-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole RX 831003, 2-(2-pentyl-2,3-dihydro-benzofuran-2-yl)-4,5-dihydro-1H-imidazole RX821002, 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline S16924, (R)-2-1-{1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolodin-3yl}-1-(4-fluorophenyl)ethanone SB 207266, (N-1-butyl-4-piperinylmethyl)-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide, hydrochloride SB 216,469, (also REC15/2739) N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4-H-1-benzopropyran-8-carboxamide monomethanesulfonate SB 224289, 5,1′-methyl-5-(2′-methyl-4′-(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-carbonyl)2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3-spiro-4′- piperidine] SB 228357, 1-[[3-fluoro-5-(3-pyridyl)phenyl]carbamoyl]-5-methoxy-6-trifluoromethylindoline SB 236057, (1′-ethyl-5-(2′-methyl-4′-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4′-piperidine]) SB 243213, 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline SB 258719, (R)-3, N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide Sch23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride sCT-(8-32), salmon calcitonin(8-32) SDF-1α, stromal cell-derived factor 1α SDZ-212-769, [Ala7]sCT-(7-32) SDZ-219-379, Ac-[Aib10,17,Lys(For)11,18,Lys(lp)24]sCT-(8-32) 4 5 2 7 10 SHU9119, Ac-Nle -c[Asp ,D- Nal ,Lys ]NH2 ACTH4-10 SNAP 5089, 2,6-dimethyl-4-(4-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid-N[3-(4,4-diphenylpiperidine-1-yl)propyl]amide-methyl ester SR 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3carboxamide HCl SR 144528, {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.20.1]heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide SR-121463A, 1-[4-(N-tert-butylcarbamoyl)-2-metoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholino ethoxy) cyclohexane]-indol-2-one, furamate Tic, tetrahydroisoquinoline-3-carboxylic acid Tic-OH, H-2′,6-L-tyrosine(Dmt)-1,2,3,4-tetrahydoquinoline-3-carboxylic acid TIPP, Tyr-Tic-Phe-Phe TIPP[ψ], H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic[CH2-NH]Phe-Phe-OH TRH, thyrotropin-releasing hormone vMIP-II, viral macrophage inflammatory protein II WAY 100,635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclohexane-carboxamide WB 4101, 2-(2,6-dimethoxyphenoxyethyl)aminoethyl-1,4-benzodioxane hydrochloride WEB2086, 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo-[4,3-a]-[1,4]-diazepin-2-yl]-1-(4-morpholinyl)-1-propanon WRC-0571, 8-(N-methylisopropyl)amino-N6-(5′-endohydroxy-endonorbornyl)-9-methyladenine XAC, xanthine amine congener