325

Index

a amidotransferases, 263 ABC. see ATP-binding cassette (ABC) – γ-glutamyl transpeptidase, 263 ABC transporters, 12, 107 amine hypothesis, 21 – effects on drug disposition, 112 amino acidpolyamine-organocation – mutations, 113 superfamily, 16 – neurological disorders, role in, 180–181 amino acid/polyamine/organocation – PET imaging, 181–183 transporter (APC), 262 – PET tracers amino acid transporters, 254 –– applications, 184–185 γ-aminobutyric acid (GABA), 24, 69 –– designing, challenges in, 184 – neurotransmission, 85 – pharmacochaperones and, 113, 114 – signaling, 73, 85 – proteins, 7 aminophospholipid, 204 – role of, 108 ammonia channel transporter (Amt) family, 7 – superfamily, 2 amyloid precursor protein (APP), 180 – from targets to antitargets, 111–113 anaesthetics, 1 absorption, disposition, metabolism and anion exchanger, 144 excretion (ADME), 253 anoctamin 1 (ANO1), 231, 233, 234 – SLC transporters, importance in, 253 – activators of, 240 acetylcholine, 41 – biophysical properties of, 234, 235 ADME. see absorption, disposition, metabolism – calcium activated chloride channel, 232 and excretion (ADME) – and cancer, 236–238 age-related insensitivity, 40 – characterization of, 232 alanine-serine-cysteine transporter 1 – as contributor to renal cyst growth, 245 (ASCT1), 260 – cystic fibrosis-related diabetes (CFRD), 232, alanine-serine-cysteine transporter 2 245 (ASCT2), 253, 260 – discovery of, 232, 233 Alisma orientalis, 212, 213 – effect on motility of human cancer cells, 237 allosteric effect – expression and physiological role of, 235, – citalopram, 29 236 – escitalopram, 28 – gene coding for, 236 allosteric mechanism, 30 – in GIST, 231 allosteric serotonin reuptake inhibitors – inhibition, during a type I asthma attack, 232 (ASRIs), 26 – inhibitors, structures of, 239 allosteric serotonin transporter – natural products, 240, 241 modulators, 28, 30 – as passenger event, 236 allosteric site, on serotonin transporter – pharmacological targeting of, 238 – localization of, 27, 28 – potential risks, of therapeutic – structure-activity relationships at, 28–30 intervention, 245, 246 alzheimer’s disease, 180 – small-molecule inhibitors of, 238–240

Transporters as Drug Targets, First Edition. Edited by Gerhard F. Ecker, Rasmus P. Clausen, and Harald H. Sitte.  2017 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2017 by Wiley-VCH Verlag GmbH & Co. KGaA. 326 Index

– structure of, 234, 239 Atractylodes macrocephala, 212, 213 – therapeutic paradigms for, 246 attention deficit hyperactivity disorder – as therapeutic target, 241 (ADHD), 30 – for tumor growth in breast and head and neck audiogenic seizure (AGS), 86 cancers, 232 autoradiography, 40 anthranilic acid, 186, 187 antiarrhythmic drugs, 1 b anticancer drugs, 109, 131 BA homeostasis, 141 antidepressant, 22 BA-mediated activation, 202 – drug, 22, 24, 56 – of FXR, 201 –– nomenclature, 22–24 β-amyloid (Aβ) clearance, 180 – possible approach to a new classification BAs. see bile acids (BAs) of, 23 basolateral membrane, 199 – SNRIs, 32 basolateral transport proteins, 199 – therapies, 22 BBB. see blood-brain barrier (BBB) antidiabetic drug BCRP. see breast cancer resistance protein – metformin, 253 (BCRP) antiepileptic drug, 180 BCS. see Biopharmaceutics Classification antihypertensive drugs, 1 System (BCS) antineoplastic agents, 17 BDL. see bile duct ligated (BDL) antiporter, 5 benign recurrent intrahepatic cholestasis APC. see amino acid/polyamine/organocation (BRIC), 200 transporter (APC) benzimidazole derivatives, 218, 219 apical (canalicular) membrane, 199 betaine/GABA transporter 1 (BGT1), 74 approved drugs, and targeted transport BGT1. see betaine/GABA transporter 1 (BGT1) proteins, 14 bile acids (BAs), 113, 119, 201, 305 Aquifex aeolicus,55 – enterohepatic cycle, 199 N-arachidonyl-glycine (NAGly), 94 bile duct epithelium, 142 ASCT1. see alanine-serine-cysteine transporter bile duct ligated (BDL), 137 1 (ASCT1) bile salt export pump (BSEP or ABCB11), 121, ASCT2. see alanine-serine-cysteine transporter 200 2 (ASCT2) bilirubin, 126–128 asthma, 231, 242 – conjugated, 144 atherosclerosis, 135 – unconjugated, 129, 280, 285 atomoxetine, 30 bioactivity data counts, 15 ATPases, 7 Biopharmaceutics Classification System ATP-binding cassette (ABC), 179 (BCS), 111 – family, 5 BLAST search, 4 – proteins, 7, 10 blood-brain barrier (BBB), 112, 179, 263 – transporters, 119, 200 (see also ABC botulinum neurotoxin A, 12 transporters) brain –– basolateral, 119 – capillary endothelial cells, 179 ––ABCC3, 136 – pharmacological sanctuary, role as, 180 ––ABCC4, 138 breast cancer resistance protein (BCRP), –– canalicular, 119, 122 108 ––ABCB1, 126 breast cancers, 232 ––ABCB4, 131 Brintellix,38 ––ABCB11, 122 British Pharmacological Society (BPS), 5 ––ABCC2, 126 BSEP. see bile salt export pump (BSEP) ––ABCG2, 133 BSEP expression, mediated by CDCA, ––ABCG5/8, 131 203 ATP-dependent xenotoxin transport BSEP gene, 203 pump, 107 Byler disease, 204 Index 327 c ChEMBL classification, 2, 11 CA. see cholic acid (CA) – ChEMBL-16, 5, 7 Ca2+/calmodulin-dependent protein kinase –– transporter hierarchy, 5 IIα (αCaMKII), 58 – ChEMBL-18, 5 Caco-2 cell, 189 – ChEMBL-19, 12, 15 cafestol, 203 – database, 5 calcium channel blockers, 109 chemoconvulsants, 87 calmodulin, 235 chenodeoxycholic acid (CDCA), 121, 201 camptothecin, 189 chloride channel, 12 canalicular membrane, 202 chloride-independent transporters canalicular transport protein BSEP – leucine transporter (LeuT), 77 (ABCB11), 203 chloride (Cl ) ion, 231 cancer, 107, 231, 243–245 – channel activation, 231 cancer cells, 131 cholangiocytes, 207 cancer development cholehepatic shunt pathway, 207 – SLC transporters in, 263 cholestasis, 119, 200, 205 cancer metabolism – disorders, 201 – amino acid transporters in, 253 cholestasis of pregnancy (ICP), 123 – solute carriers in, 253–255 cholestatic diseases, 204 – targets, 260–263 cholestatic patients, 119 –– ASCT2, 260–262 – clinical management of, 145 –– LAT-1, 262–263 cholesterol, 201 cancer pathogenesis – lowering drug, 12 – SLC transporters, role in, 253 cholic acid (CA), 121  cancer-related transporters Cipralex ,26 – ASCT2, 264 cirrhosis, 113, 119, 130, 132, 210, 221, 298, 301 – LAT-1, 264 citalopram, 26–30, 38 cancer therapy, 15 c-Jun N-terminal kinase (JNK) pathways, 202 – transporter targeting in, 263 cladograms, 15 CAR. see constitutive androstane receptor classified membrane transport proteins in (CAR) IUPHAR/BPS, TCDB, and ChEMBL-16, CARM-1 (coactivator-associated arginine (“R”) overlap of, 11 methyl transferase-1), 207 clinical PET studies, 40 cation-chloride cotransporter (CCC) family clinical trials, 15, 82, 94, 95, 126, 140, 144, 221, (SLC 12), 1 240, 241, 243, 300 CDCA. see chenodeoxycholic acid (CDCA) clomipramine, 27, 56, 59 cell swelling, 125 cloxacillin, 203 central nervous system (CNS)-targeted Clustal Omega, 16 drugs, 180 cocrystallization, 78 cerebral ABC transporters cognitive dysfunction, 22 – PET tracers, 185–191 combined SERT inhibitors – –– radiolabelled BCRP substrates, 189 and 5-HT1A receptor antagonists, 37 –– radiolabelled dual P-gp/BCRP Commiphora mukul, 211 substrates, 189–190 conicasterol E, 213, 214 –– radiolabelled MRP1 substrates, 190–191 conjugated steroid metabolites, 204 –– radiolabelled P-gp inhibitors, 187–189 constipation, 15 –– radiolabelled P-gp substrates, 185–187 constitutive androstane receptor (CAR), 120, cerebrospinal fluid (CSF) biomarkers, 24 121, 125 CFRD. see cystic fibrosis-related diabetes contradictory classification in TCDB, IUPHAR/ (CFRD) BPS, and ChEMBL-16, 7, 8 CFTR. see cystic fibrosis transmembrane coumestrol, 214, 215 regulator (CFTR) cyclic adenosine monophosphate (cAMP), 231 channels of ChEMBL-16, 11 cyclosporine A, 203 328 Index

Cymbalta,32 –– target–template alignment, 258 CYP7A1 expression, 219 –– template selection, 256–258 cystic fibrosis (CF), 113, 231, 241, 242 – virtual screening, 255 – caused by, 241 drug-induced alterations, 200 – mucus production, 232 drug-induced liver injury (DILI), 113 – treatment of, 242 drugs, pharmacokinetics of, 134 cystic fibrosis-related diabetes (CFRD), 245 drug targets, 69 cystic fibrosis transmembrane conductance – in SLC classification, 15 regulator (CFTR) protein, 12, 231 drug toxicity, 131 cytokines, 128, 129, 131, 138, 202, 232, 242 drug transporters, 131 cytosolic calcium, 234 – mutations in, 253 drug–transport interactions, 200 d Dubin–Johnson syndrome, 113, 127, 137, 200 Dalcipran,32 duloxetine, 25, 32, 35 DAT (dopamine transporter), 22 database database, 2 e 12-O-deacetyl-12-epi-19-deoxy-21- EBI Web server, 16 hydroxyscalarin, 213 edivoxetine (LY2216684), 30, 31 dendritic cells, 139 Effexor,32 Dendronephthya gigantean, 214 EGFR. see epidermal growth factor receptor’s depression, 21, 180 (EGFR) – and antidepressant drugs, disease biology endogenous modulator, 201 of, 24, 25 enterocytes, 205 desipramine, 28, 56 enterohepatic circulation, 202 diabetic nephropathy, 201 Enzyme Commission (EC) classification, 2 12,24-diacetoxy-deoxyscalarin, 213 epidermal growth factor receptor’s diarrhea, 212, 213, 231, 232, 236, 242, 243, 246 (EGFR), 190 dietary supplementation, 136 (-)-epigallocatechins-3-gallate (EGCG), 214, DILI. see drug-induced liver injury (DILI) 215 dimethoxytetrahydroisoquinolinylethyl, 186, Epilepsy, 85 187 – GABAergic system in, 85 discrete distribution, 24 – GAT role in, 86 DisGeNET, 15 epileptic brain tissue, 180 diterpene compound, 203 erlotinib, 180, 190 diuretics, 1, 14 ER-8 response element, 205 DNA-binding domain, 205 escitalopram, 25, 26 docking programs, 259, 260 – allosteric effect, 27 dopamine (DA) uptake, 31 – antagonistic effect on, 26 Drosophola melanogaster,56 – dissociation, 29 DrugBank, 1 – internalization induced by, 27 drug design – mutations in S2 pocket, 28 – structure-based – 1-naphthyl derivative of, 28 –– in silico methods for ethynylestradiol, 138 ––homology modeling, 256–259 eukaryotic dopamine transporter, 72 ––ligand prediction, 259–260 European Medicine Agency (EMA), 32 ––transporter dynamics, 259 extracellular neurotransmitter, 70 drug development ezetimibe, 12 – small-molecule ligands, role in, 260 drug discovery, 255 f – homology modeling, 255 familial intrahepatic cholestasis 1 (FIC1), 204 –– model building and assessment, 258 farnesol, 201 –– model refinement, 258 Fexaramine and derivatives, 217 –– model validation, 258–259 fibrosis, 144, 210. see also Cystic fibrosis Index 329

– antifibrotic effects in a rat model of liver, 143 – molecular pharmacology of, 73–78 – multiple FXR-mediated activities and, 210 –– transporter structure–function – PPARγ agonist troglitazone decrease, 144 studies, 76–78 – tetrachloride-induced, 143 – nomenclature of, 72 Fisher rat thyroid (FRT) cell model, 239 – subtypes, 72, 75, 85 fluoxetine, 26–28, 42 –– modeling of, 76 fluvoxamine, 26 gallstone disease, 201 folding sensor, 58 Ganoderma lucidum, 212 fold recognition methods gastrointestinal stromal tumor (GIST), 231 – HHPred, 257 GAT. see GABA transporters (GAT) – Promals3D, 257 GAT inhibitors, 73, 74 Fructus ligustri lucidi, 212 – subtype-selective binding of, 77 F-type and V-type ATPases, 5 GAT substrates, 74 function vs. sequence similarity, 7 GBM. see glioblastoma multiforme (GBM) FXR-activated pathway, 207 gefitinib, 180, 190

FXR activity (EC50,IC50) of triterpene gene expression, 144 derivatives, 212 gene mutations, 133 FXRα gene, 207 GeneOntology, 11 FXR450 and derivatives, 217, 218 gene promoters, 205 FXR and PXR receptors, 213 genetic and structural properties of FXR, FXR gene knockout, 204 207–209 FXR ligands, 209 genetic polymorphism, 188 – natural compounds and derivatives, 209 GIST. see gastrointestinal stromal tumor (GIST) –– bile acids and derivatives, 209–211 glibenclamide, 203, 282 –– guggulsterones, 211, 212 glioblastoma multiforme (GBM), 260 –– miscellaneous natural compounds and glucocorticoid receptor (GR), 140 derivatives, 214, 215 glucose homeostasis, 201 –– sterols and polyhydroxylated sterol glutamate, 24, 41, 62, 77, 86, 90, 259, 261 derivatives, 213, 214 gluthatione, 204 –– triterpenes, 212, 213 Gly. see glycine (Gly) – from virtual screening campaigns, 220 glycine (Gly), 17, 54, 56, 69, 71, 94 FXR-mediated inhibition glycinergic neurons, 95 – OATP-C expression, 207 glycinergic synapses, 90 FXR-mediated mechanisms, 202 glycine transporters. see Gly transporters FXR null mice, 201 (GLYT) FXR/RXRα heterodimer complex, 203, 204 glycocholic acid, 122 FXR/TGR5 agonist, 210 glycosylation, 77, 109 GLYT. see Gly transporters (GLYT) g GLYT inhibitors, 92–94 GABA. see γ-aminobutyric acid (GABA) – GLYT1 inhibitors, 92–93 GABA transporters (GAT), 70, 73–89 – GLYT2 inhibitors, 93–94 – GABA uptake inhibitors – therapeutic potential of, 94–95 –– medicinal chemistry of, 78–85 Gly transporters (GLYT), 70, 90 – GAT inhibitors, 86 – inhibitors, 92–94 –– therapeutic potential of, 85–89 –– therapeutic potential of, 94–95 ––animal models of anticonvulsant – localization of, 90 action, 86–87 – molecular pharmacology of, 91–92 ––GAT inhibitors and epilepsy, 87–89 – nomenclature of, 72 ––role in epilepsy/anticonvulsive – physiology of, 90–91 therapy, 85–86 –– function of GLYT1 at excitatory ––therapeutic potential of GAT in the synapses, 90–91 recovery of stroke, 89 –– lessons from GLYT knockout mice, 91 – localization of, 73 – subtypes, 73, 90 330 Index

gout, 113 5-HT receptor modulating mechanisms, 25 G protein-coupled receptors (GPCRs), 5 5-HT reuptake inhibitor, 27 GR. see glucocorticoid receptor (GR) 5-HT uptake, 31 guggulsterones, 211 – and allosteric effect at human SERT and – E- and Z-, 209, 211 citalopram analogs, inhibition of, 29 GW4064 (7, FXR agonist), 203 HUGO Gene Nomenclature Committee GW4064-related compounds, 216 (HGNC), 6 human ASBT transport protein, 207 h human membrane transport protein head and neck squamous cell carcinoma – classification of TCDB, IUPHAR/BPS, and (HNSCC), 232 ChEMBL-19 in contrast, 13 hepatic cell, 199 – overview of, 9 hepatic cholestasis, 201 human P-glycoprotein, inhibitors of, 111 hepatic transporters, 207 human transport protein families, simplified hepatobiliary transporters, 202 overview of, 10 – regulatory system of, 202 hydropathy analysis, 234 hepatobiliary transport system, 200, 201, 202, hypercholesterolemia, 15 206 6 Hz psychomotor seizure test, 86 hepatobiliary transport system by FXR – regulation of, 201 i hepatocyte nuclear factor (HNF), 136 IBD. see inflammatory bowel disease (IBD) hepatocytes, 199, 204 IL4, 232 hepatotoxic effect, 203 ileal bile acid-binding protein (IBABP), 201, hereditary cholestatic syndromes, 200 205, 219 heterodimer complex FXR/RXRα, 201, 203 imipramine, 21, 24, 26, 29 heterogeneous group, of disease biologies, 24 inflammatory bowel disease (IBD), 139 heteroreceptors, 41 inhibitory neurotransmitters, 70, 95 HGNC gene families, 5 – γ-aminobutyric acid (GABA), 70 Hill coefficient, of calcium binding, 234 – glycine (Gly), 70 hippocampus, 41, 42 inhibitory neurotransmitter transporters, 96 histamine, 41 International Union of Basic and Clinical HIV protease inhibitors, 129 Pharmacology (IUPHAR)., 5 HNF-1α-binding elements, 207 intrahepatic cholestasis of pregnancy HNF-4α homodimer, 206 (ICP), 124, 127, 132 HNF-1α ligand-independent transcription ion channels, 5 factor, 206 – proteins, 234 homology modeling, 255 – receptors, 70 – model building and assessment, 258 iproniazid, 21, 23 – model refinement, 258 isoxazole, 215, 216 – model validation, 258–259 IUPHAR/BPS, 7 – target–template alignment, 258 – based classification, 12 – template selection, 256–258 – level, 7 hormone-responsive elements, 206 IUPHAR/BPS Guide to PHARMACOLOGY, 5 H-symporter, 5 IUPHAR database, 5

5-HT1A autoreceptor antagonist, 37 ivacaftor, 15, 108 5-HT1A receptor ivermectin, 214, 215 – agonist, 37, 38 Ixel,32 – antagonism, 38 – functional efficacy, 37 k

5-HT1B receptor, 41 ketamine, 22 5-HT2C receptor antagonist, 22 kinase inhibitors, 107. see also Tyrosine kinase 5-HT1D and 5-HT7 receptor antagonism, 41 inhibitors 5-HT levels, in brain, 26 kinases, catalytic receptors, 5 Index 331 l membrane-inserted human SERT model, large neutral amino acid 1 transporter 57 (LAT-1), 262 membrane transporters, 199 LAT-1. see large neutral amino acid 1 membrane transport protein, 2, 4, 6, 7, 11, 12 transporter (LAT-1) – databases, 2 LAT-1 substrates, 263 merged top-level transporter classification, – acivicin, 263 7–11 – fenclonine, 263 MES. see maximal electroshock (MES) leucine transporter (LeuT), 27, 72 methylation of FXR at Lys206, 203 – translocation pathway, 59 N-methyl-D-aspartate receptors LeuT. see leucine transporter (LeuT) (NMDAR), 69 LeuT-fold, 57 midecamycin, 203 levetiracetam, 10 milnacepran, 32 levomilnacipran, 32 milnacipran, 32 Lexapro,26 mirtazepine, 22, 23 LG100268 (6, RXR agonist), 203 mitogen-activated protein kinase ligand-activated FXR/RXRα, 205 (MAPK), 202, 237 ligand-binding affinity, 260 molecular docking, 259, 261 ligand-gated ion channels, 5 molecular neuroscience, 53 ligand prediction monoamine oxidase (MAO)-A and -B, 21 – ligand selection, 260 monoamine oxidases, 24 – virtual screening, 259–260 monoamine receptors, 37 –– models used for, 262 monoaminergic neurotransmitter levels, 24 lipid homeostasis, 133, 201 monoamines, 24 lipophilic radioactive metabolites, 31 – transporter inhibition, 22, 36 lithogenicity, 132 monoamine transporters, 22, 24 liver diseases, 127, 132, 138, 144, 200, 204, 217, monoclonal antibodies, 107 301, 303 monotherapy, 30 liver regeneration, 143, 201 – UDCA, 142 liver transporters, 199 MRP2 (ABCC2) canalicular transporter, liver X receptor (LXR), 136 203 LLC-PK1 MDR cells, 185 MRP4 expression, 204 LXR. see liver X receptor (LXR) MRP2 gene, 203 MRP4 gene m – expression, 204 major depressive disorder (MDD), 21, 22, 24, MRPs. see multidrug resistance-associated 30, 32, 35, 38 proteins (MRPs) major facilitator superfamily (MFS), 5, 255, MRP4 (ABCC4) transporter, 204 258 MT2 receptor agonists, 22 mammalian chloride channels, 232 multidrug resistance-associated proteins – mechanism of activation, 232, 233 (MRPs), 179 MAPK. see mitogen-activated protein kinase multidrug resistance protein 1, 110 (MAPK) multidrug resistance-related protein 1 Marine echoderms, 214 (MRP1), 108 Marine sponges, 212 multidrug-resistant tumor cells, 109 marketing authorization (MA), 32 multidrug transporters, 129 maximal electroshock (MES), 86 multimodal antidepressants, 37 – test, 86 – vortioxetine, 25 Mdr1a/b-/-mice, 186 multimodal drugs, 36 MDR3 (ABCB4) flippase protein, 204 – approach, 24 melatonin (MT)1 and MT2 receptor multiple sequence alignments, 15 agonists, 22 multitarget drugs, 32, 33 membrane depolarization, 231 mutational studies at S1 site, 28 332 Index

n NSS. see neurotransmitter:sodium symporter + Na -channels, 12 (NSS) NAGly. see N-arachidonyl-glycine (NAGly) NTCP. see taurocholate cotransporting Na+/H+ antiporters (SLC 9), 1 polypeptide (NTCP) + + Na /K ATPases, 1 NTCP (sodium/taurocholic acid cotransporter (naphthalen-1-ylsulfanyl)acetonitrile, 30 protein), 206 1-naphthyl and 1-indole derivatives, 30 NTCP expression, 206 Na-symporter, 5 nuclear hormone receptors (NHRs), 5 nausea, 22 nuclear localization, of FXR, 204 NCor (nuclear corepressor), 207 nuclear receptors, 120, 205, 206 NE and 5-HT receptor modulator, 22 – canonical structure of, 208 neuroadaptive processes, 24 – as drug targets, 140 neurogenesis, 24, 25, 41, 42 – PPARα, 133 neurological disorders – as regulators of BA metabolism, 121 – GABA-mediated synapses, role in, 85 nucleotide binding domains (NBDs), 107, 108, neuronal plasticity, 24, 25, 42 122, 128, 132, 138 neurotransmission, 40, 53, 69, 70, 79, 85 – 5-HT, 41 o – NMDAR-mediated, 91 OATP-C gene, 204, 206 – noradrenergic, 25 OATP8 glycoprotein, 204 – regional modulation, 40 obeticholic acid, 209 neurotransmitters, 21, 24, 69 obstructive cholestasis, 122, 125, 128, 130, 134, – γ-aminobutyric acid (GABA), 69 137, 138 – glycine (Gly), 69 OCT1. see organic cation transporter 1 (OCT1) – monoamines dopamine, 69 octyl-glucoside, 59 – norepinephrine, 69 oligopeptides, 204, 271 – serotonin, 69 Open PHACTS project, 11 neurotransmitter:sodium symporter ophiuroids, 213 (NSS), 53, 255 organic anions, 206 neurotransmitter systems, 24 organic anion transporter proteins neurotransmitter transporters, 69, 256 (OATPs), 204 – binding site proper, 59–61 organic cation transporter 1 (OCT1), 253 – transport cycle, 61–63 organic solute transporter alpha/beta New Drug Application (NDA), 32 (OSTα/OSTβ), 199, 205 Niemann-Pick C-1-like protein, 12 oxidative stress, 125, 128, 309 γ- nitrogen, 78 NMDA receptor antagonist, 22 p Nomenclature Committee of the International pancreatic duct epithelial cells, 138 Union of Biochemistry and Molecular paroxetine, 26 Biology, 2 PBC. see primary biliary cirrhosis (PBC) nonsteroidal compounds, 215 PC. see phosphatidylcholine (PC) – benzimidazole derivatives and retinoic peptide transporter acid-related compounds, 218, 219 – PEPT1, 259 – fexaramine and derivatives, 217 PET. see positron emission tomography (PET) – FXR450 and derivatives, 217, 218 PET tracers, 182, 184 – GW4064 and derivatives, 215–217 – chemical structures, 182 – virtual screening campaigns, 219–221 P-glycoprotein (P-gp) inhibitors, 107 norepinephrine and dopamine reuptake – discovery of, 108 inhibitors, 36 – paradigm model system for, 110 norepinephrine reuptake inhibitors, 29 – physiological function of, 111 – SNRIs, 22, 32 – in vivo and in vitro concentration of, 100 norepinephrine transporter (NET), 21, P-gp function, small-animal PET imaging 256 of, 183 Index 333

P-gp inhibitor cyclosporine A, 185 – [11C] laniquidar, 189 pharmacochaperone, 108 – [18F] labeled elacridar, 188 pharmacokinetics, 129 – [18F] labeled tariquidar, 187–188 pharmacological characterization of FXR, 200 radiolabelled P-gp substrates pharmacological management, 200 – [11C] loperamide, 186–187 PHARMACOLOGY database, 5 – [11C]-N-desmethyl-loperamide, 186–187 pharmacology-driven IUPHAR/BPS – racemic [11C]verapamil, 185–186 classification, 2 – (R)-[11C]verapami, 185–186 phosphatidylcholine (PC), 132 radiolabelled transporter substrates, 181 phosphatidylserine, 204 radiotracers, 181 phospholipid flippase (MDR3 or ABCB4), 200 Raf kinase, 190 phospholipids, 204 R-citalopram, 26 phosphorylation, 204 (R)- [11C]verapamil phylogenetic heterogeneity, 10 – baseline scans, 186 pindolol, 37 – metabolism, 186 PKC. see protein kinase C (PKC) – transportation, 186 placebo–controlled MDD study, 30 refractory epilepsy, 180 pleiotropic activities, of FXR, 201 retinoic acid-related compounds, 218, 219 PMRT-1 (protein arginine (“R”) methyl reuptake blockers, 26 transferase-1), 208 Rh ammonium transporter family (SLC 42), 7 polymorphisms, 129 Rh glycoproteins, 7 positron emission tomography (PET), 181 rifampicin, 203 postsynaptic receptors, 21, 53 rocking bundle model, 62 post-translational modification, 203 RXRα (NR2B1) nuclear receptor, 206 post-translational phosphorylation, 204 presynaptic inhibitory heteroreceptors, 40 s presynaptic neurons, 53 S1-binding pocket, 60 primary biliary cirrhosis (PBC), 126, 200. see scaffold domain, 62 also cirrhosis Schisandra glaucescens diels, 212 primary sclerosis cholangitis (PSC), 200 schizophrenia, 54, 94, 180 progesterone, 40 – NMDAR hypofunction, role in, 94 progressive familial intrahepatic cholestasis scPTZ. see subcutaneous pentylenetetrazol (PFIC1-3), 200 (scPTZ) proinflammatory cytokines (IL-1β, TNFα), 202 selective allosteric serotonin transporter proline, 59 modulator, 27 prophylactic therapy, 132 selective bile acid receptor modulators protein composition, 199 (SBARMs), 212 Protein Data Bank (PDB), 2 selective inhibitors, 95 protein kinase C (PKC), 27, 125 selective NE reuptake inhibitors, 31 proton pumps, 1 selective norepinephrine reuptake protozoal channels, 2 inhibitor, 30, 31 P-type ATPases, 5 selective serotonin reuptake inhibitors – protein, 200 (SSRIs), 22, 26, 28 S-enantiomer, 26 q serotonin quality of life, 22 – and dopamine reuptake inhibitors, 36 – norepinephrine, and dopamine reuptake r inhibitors, 33–35 radiolabelled BCRP substrates – and norepinephrine reuptake inhibitors, 32 – [11C]dantrolene, 189 serotonin (5-HT) transporter (SERT), 21 radiolabelled P-gp inhibitors – inhibitor, 38 – [11C] labeled elacridar, 188 – occupancy, 40 – [11C] labeled tariquidar, 187–188 sertraline, 26–28 334 Index

sexual dysfunction, 22 structure of INT-747 derivatives SHP and BSEP gene, 214 – and activities (EC50) at FXR receptor, 209 SHP (NR0B2) atypical nuclear receptor, 205 subcutaneous pentylenetetrazol (scPTZ), 86 SHP structural properties, 205 – test, 86 single-target drugs, 26 substantial medicinal chemistry, 200 Sinularia, 214 substrate-like behavior, 183 SLC. see solute carrier transporters (SLC) substrate transport SLC transporters – transporter-mediated, 70–71 – in cancer metabolism, 254 subtype-selective inhibitors, 74 – in cancer pathogenesis, 253 sulfated polyhydroxysterols, 213 – counterparts in TCDB, 7 synapses – in drug absorption, disposition, metabolism – GABAergic and glycinergic and excretion (ADME), 253 –– inhibitory neurotransmission at, 70 – members counterparts in TCDB, 6 synaptic cleft, 53 – pseudosymmetry of, 259 synaptic transmission, 70 – series, 6, 7 synaptosomal vesicle fusion pore (SVF-Pore) SLC6-transporters, 62 family, 12 – crystal structures, 55–59 – involvement in health and disease, 54 t – substrate-binding site, 61 talopram, 29 small heterodimer partner (SHP), 201 Tangier disease, 113 sodium-dependent transporter (NTCP or tauro-CA, 203 SLC10A1), 199 tauro-CDCA, 203 sodium-independent large organic anion taurocholate cotransporting polypeptide transporters (SLCO), 107 (NTCP), 120 sodium-independent organic anion TCDB class 1, 2, 4, and 8, 7 transporters (OATPs or SLC21A), 199 theonellasterol G, 214 sodium-potassium ATPase, 61 Theonella swinhoei, 213, 214 solute carrier class (SLC), 107 therapeutic approaches, 24 solute carrier 6 family (SLC6) neurotransmitter therapy-refractory epilepsy, 184 transporter, 53 thermal hyperalgesia, 95 solute carriers, 69 threonine, 204 – superfamily 6 of, (SLC6), 69 tiagabine, 74, 78, 85, 87, 89 solute carrier transporters (SLC), 253 – epilepsy, efficacy of, 87 somatodendritic autoreceptors, 41 TM. see transmembrane (TM) sorafenib, 180, 190 TMEM16A. see transmembrane protein with soy lipids, 214 unknown function 16 (TMEM16A) spare transporter effect, 183 topotecan, 189 SRC-1 (steroid receptor coactivator 1), 207 total parenteral nutrition (TPN), 122 SSRI antidepressants, 26 TPN. see total parenteral nutrition (TPN) SSRI citalopram, 29 transcriptional activity, 204, 206 STAR*D (Sequenced Treatment Alternatives transcriptional factors, 207 to Relieve Depression) trials, 22 transcriptional inhibitors, 206 steroid-binding pocket, 209 transmembrane (TM), 72 steroids, 205 – domains (TMDs), 108 Stratera,30 – helices, 56 stroke, GAT, therapeutic potential in, 89 – sodium gradient, 53, 61 structural modifications of bile acid – transport activity, 11 scaffold, 209 transmembrane protein with unknown structure–activity relationship (SAR) function 16 (TMEM16A), 233 studies, 214 transporter as drug targets, 12 structure-based ligand discovery Transporter Classification Database – computational methods used in, 264 (TCDB), 2, 4 Index 335 transporter classification system, 2 US Food and Drug Administration (FDA), 30 transporter collections – black box warning on atomoxetine, 30 – with a focus on human membrane transport proteins, 3 v transporter family, 4 van der Waals interactions, 210 transporter-overexpressing cell lines, 188 vascular reactivity, 201 transporter proteins, 55 VDR. see vitamin D receptor (VDR) transporters, 2, 4, 5, 11, 12, 15 venlafaxine, 32 – heterogeneity of, 95 vesicular transporters, 62 transporter-selective radiotracers, 183 vilazodone, 37, 38 – PET radiotracer, 184 vincristine, 109, 129 transport proteins, 11, 199 vitamin D receptor (VDR), 122 transport system 2.A.22.6.3 voltage-gated ion channels, 5 – as an example of the TCDB classification, 4 vortioxetine (Lu AA21004), 38, 39, 40, 42 tricyclic antidepressant (TCA), 21 – antidepressant and anxiolytic properties, triglycerides, 201 40  Trintellix ,38 – 5-HT3 receptor antagonism, 41 triterpenes, 212 – increases DA in prefrontal cortex, 41 troglitazone, 203 – originally designed to increase 5-HT tryptophan, 59 neurotransmission, 41 tumor development, multiple amino acid – receptor activities result in different transporters in, 264 modulation, 41 tumorigenesis, 201 – target occupancy, dose relations determined tumor therapy, 107 by, 40 tyrosine kinase inhibitors, 180, 190 – in vitro binding affinities and functional – cancer treatment, role in, 180 efficacy of, 39 tyrosine transporters, 55 VX-661 and VX-809, chemical structure, 114 u x UDCA. see ursodeoxycholic acid treatment xenobiotics, 133, 204 (UDCA) unconjugated hyperbilirubinemia, 285 y uniprot, 5, 15 yeast transport protein database, 2 UniProt accession number, 4 ursodeoxycholic acid treatment (UDCA) z – in cholestatic liver disease, 144 zinc binding site, 58