Glycine Transporters and Their Inhibitors 245 88. Bozzoli A, Branch CL, MacRitchie JA, Marshall HR, Porter RA, Spada S (2006) International Patent Application WO 2006 067 437 89. Branch CL, Marshall H, MccRitchie J, Porter RA, Spada S (2006) International Patent Application WO 2007 080 159 90. Coulton S, Gilpin ML, Porter RA (2006) International Patent Application WO 2007 113 309 91. Anderton CL, Clapham D, Keel TR, Kindon LJ (2007) International Patent Application WO 2007147 831 92. Coulton S, Gilpin ML, Porter RA (2007) International Patent Application WO 2007 147 834 93. Coulton S, Gilpin ML, Porter RA (2007) International Patent Application WO 2007 147 836 94. Gentile G, Herdon HJ, Passchier J, Porter RA (2007) International Patent Application WO 2007 147 838 95. Coulton S, Gilpin ML, Porter RA (2007) International Patent Application WO 2007 147 839 96. Sekiguchi Y, Okubo T, Shibata T, Abe K, Yamamoto S, Kashiwa S (2008) International Patent Application WO 2008 018 639 97. Blackaby WP, Huscroft IT, Keown LE, Lewis RT, Raubo PA, Street LJ, Thomson CG, Thomson J (2006) International Patent Application WO 2006 134 341 98. Blackaby WP, Castro Pineiro JL, Lewis RT, Naylor EM, Street LJ (2006) US Patent Application US 0 276 655 99. Blackaby WP, Castro Pineiro JL, Lewis RT, Naylor EM, Street LJ (2006) International Patent Application WO 2006 131 711 100. Blackaby WP, Castro Pineiro JL, Lewis RT, Naylor EM, Street LJ (2006) International Patent Application WO 2006 131 713 101. Blackaby WP, Fletcher SR, Jennings A, Lewis RT, Naylor EM, Street LJ, Thomson J (2006) International Patent Application WO 2006 067 529 102. Lindsley CW, Wisnoski DD, Wolkenberg SE (2006) International Patent Application WO 2006 039 221 103. Burnds HD, Hamill, TG, Lindsley CW (2007) International Patent Application WO 2007 041 025 104. Hallett D, Lindsley CW, Naylor EM, Zhao Z, Theberge CR, Wolkenberg SE, Nolt BM (2007) International Patent Application WO 2007 053 400 105. Blackaby WP, Lewis RT, Naylor EM (2007) International Patent Application WO 2007 060 484 106. Lindsley CW, Zhao Z, Leister WH, O’Brien J, Lemaire W, Williams DL, Chen T-B, Chang RSL, Burno M, Jacobson MA, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Tsou NN, Duggan ME, Conn PJ, Hartman GD (2006) ChemMedChem 1:807 107. Bradley DM, Branch CL, Brown BJ, Chan WN, Coulton S, Dean AW, Doyle PM, Evans B, Gilpin ML, Gough SL, MacRitchie JA, Marshall HR, Nash DJ, Porter RA, Stasi LP (2006) International Patent Application WO 2006 094 840 108. Bradley DM, Branch CL, Chan WN, Coulton S, Dean AW, Doyle PM, Evans B, Gilpin ML, Gough SL, MacRitchie JA, Marshall HR, Nash DJ, Porter RA, Ward SE (2006) International Patent Application WO 2006 094 842 109. Bradley DM, Branch CL, Brown BJ, Chan WN, Coulton S, Dean AW, Doyle PM, Evans B, Gilpin ML, Gough SL, MacRitchie JA, Marshall HR, Nash DJ, Porter RA, Stasi LP (2006) International Patent Application WO 2006 094 843 110. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) US Patent Application US 0 149 062
246 R. Gilfillan et al. 111. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) International Patent Application WO 2006 061 135 112. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) International Patent Application WO 2006 072 436 113. Bubendorf A, Deynet-Vucenovic A, Diodone R, Grassmann O, Lindenstruth K, Pinard E, Rohrer FE, Schwitter U (2008) International Patent Application WO 2008 080 821 114. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) US Patent Application US 0 128 713 115. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) US Patent Application US 0 160 788 116. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) US Patent Application US 0 167 023 117. Jolidon S, Narquizian R, Norcross RD, Pinard E (2006) International Patent Application WO 2006 082 001 118. Jolidon S, Narquizian R, Norcross RD, Pinard E (2007) International Patent Application WO 2007 147 770 119. Dean AW, Porter RA (2007) International Patent Application WO 2007 014 762 120. Coulton S, Marshall H, Nash DJ, Porter RA (2007) International Patent Application WO 2007 104 775 121. Coulton S, Marshall H, Nash DJ, Porter RA (2007) International Patent Application WO 2007 104 776 122. Branch CL, Marshall H, Nash DJ, Porter RA (2007) International Patent Application WO 2007 116 061 123. Ahmad NM, Lai JYQ, Andreotti D, Marshall HR, Nash DJ, Porter RA (2008) International Patent Application WO 2008 092 876 124. Ahmad NM, Lai JYQ, Marshall HR, Nash DJ, Porter RA (2008) International Patent Application WO 2008 092 877 125. Jolidon S, Narquizian R, Norcross RD, Pinard E (2007) International Patent Application WO 2007 101 802 126. Bozzoli A, Branch CL, Marshall H, Nash DJ (2006) International Patent Application WO 2006 002 956 127. Rahman SS, Coulton S, Herdon HJ, Joiner GF, Jin J, Porter RA (2007) Bioorg Med Chem Lett 17:1741 128. Jolidon S, Narquizian R, Pinard E (2008) International Patent Application WO 2008 022 938 129. Jolidon S, Narquizian R, Pinard E (2008) International Patent Application WO 2008 025 694 130. Michardy SF, Lowe JA (2006) International Patent Application WO 2006 106 425 131. Lowe JA, Sakya SM, Sanner MA, Coe JW, McHardy SF (2008) International Patent Application WO 2008 065 500 132. Lowe J, Drozda S, Qian W, Peakman M-C, Liu J, Gibbs J, Harms J, Schmidt C, Fisher K, Strick C, Schmidt A, Vanase M, Lebel L (2007) Bioorg Med Chem Lett 17:1675 133. Morita K, Motoyama N, Kitayama T, Morioka N, Kifune K, Dohi T (2008) J Pharmacol Exp Ther 326:633 134. Caulfield WL, Collie IT, Dickins RS, Epemolu O, McGuire R, Hill DR, McVey G, Morphy JR, Rankovic Z, Sundaram H (2001) J Med Chem 44:2659 135. Morphy JR, Rankovic Z (2003) International Patent Application WO 2003 010 132
Glycine Transporters and Their Inhibitors 247 136. Isaac M, Slassi A, Da Silva K, Arora J, MacLean N, Hung B, McCallum K (2001) Bioorg Med Chem Lett 11:1371 137. Isaac M, O’Brien A, Slassi A, Da Silva K, Arora J, MacLean N, Hong B, McCallum K, Bell S, Mead E, Devivo M, Schumacher R, Lechner S, Hopper A, Orgnyanov V, Tehim A (2003) PharmaChem 2:38 138. Ho K-K, Appell KC, Baldwin JJ, Bohnstedt AC, Dong G, Guo T, Horlick R, Islam KR, Kultgen SG, Masterson CM, McDonald E, McMillan K, Morphy JR, Rankovic Z, Sundaram H, Webb M (2004) Bioorg Med Chem Lett 14:545 139. Ho K-K, Baldwin JJ, Bohnstedt, Kultgen SG, McDonald E, Guo T, Morphy JR, Rankovic Z, Horlick R, Appell KC (2004) US Patent Application US 0 167 119 140. Laborde E, Villar HO (2002) International Patent Application WO 2002 064 135 141. Harada N, Hikota M (2006) International Patent Application WO 2006 080 477 142. Wolin RL, Venkatesan H, Tang L, Santillan A, Barclay T, Wilson S, Lee DH, Lovenberg TW (2004) Bioorg Med Chem 12:4477 143. Wolin RL, Santillan A, Barclay T, Tang L, Venkatesan H, Wilson S, Lee DH, Lovenberg TW (2004) Bioorg Med Chem 12:4493 144. Barclay TK, Santillan A, Tang LY, Venkatesan H, Wolin RL (2005) International Patent Application WO 2005 044 810 145. Wolin RL, Santillan A, Tang L, Huang C, Jiang X, Lovenberg TW (2004) Bioorg Med Chem 12:4511 146. Huang CQ, Lovenberg TW, Santillan A, Tang LY, Wolin RL (2005) US Patent Application US 0 049 239 147. Huang CQ, Lovenberg TW, Santillan A, Tang LY, Wolin RL (2005) International Patent Application WO 2005 021 525
Subject Index ABC transporters 175 – cancer therapy 37 – multidrug resistance, cancer chemotherapy 37 ABC-type uptake permeases 35 Acenta series 145 Acriflavine resistance protein B (AcrB) 31 Active transport 22 Addiction medication discovery 95 Adriamycin, ABCB1 transporter 37 Alanosine 210 Amino acid transporters, excitatory (EAATs) 190 Aminoadipate/aminopimelate 209 Aminocyclohexenes 60 Aminoindanes 85 Aminotetralins 85 Amitriptyline 55, 133 Amphetamine 4 AMRI CNS-1&2 145 Antibiotic treatment 39 Anticancer agents 2 Antidepressants 20, 40, 132, 151, 158, 164, 171 – tricyclic (TCAs) 54, 131, 151, 165 Antihistaminic effects 114 Antimuscarinic effects 114 Antioxidant-responsive elements (ARE) 213 Antiport 3, 23 Antiporters 21, 30, 43 Archaeal glutamate transporter homologue 6, 34, 192 1-Aryl-3,4-dihydro-1H-quinolin-2-ones 88 Aryloxymorpholines 166 Aryloxypropanamine analogues 85 Arylthiomethyl morpholines 81 3-Aryltropanes 97 Aspartamides 203 Aspartate 187, 188 – amide derivatives 197 – substituted analogues 194 Aspartate analogues, β-substituted 194 Aspartate-β-hydroxamate 194 Aspartylamide 187 Atomoxetine 85, 55, 133 – analogues 85 ATP-binding cassette family 2, 22, 35, 157, 175 Atropine 115 Attention deficit hyperactivity disorder (ADHD) 8, 55, 133, 164 2-Benzhydryl-5-benzylaminotetrahydropyran-4-ol derivatives 148 Benzodiazepin/opiate binding 137 Benzoylaspartates 203 Benztropinamines 105 Benztropine 9, 95 – self-administration 112 Benztropine analogues 97 – 3-substituted 100 – 6/7-substituted 105 – molecular effects 120 – N-substituted 100 Benzylaspartates 203 Benzylic amines 65 Benzyloxyaspartate 187 – analogues 195 Bicifadine 136 Bicycloheptanes 143 Biphenyl pyrrolidine analogues 86 Blockbuster antidepressants 151 Bupropion 3, 136, 137 Carbomethoxy-3β-phenyl tropanes 58 Carboxycyclobutyl glycines (CBGs) 199
250 Subject Index Carboxycyclopropyl analogues 198 Carvedilol 176 Catecholamines 164 – theory of depression 132 Ceftriaxone 207 Chemical signalling 2 4-(4-Chlorophenyl)piperidines 89 Chlorpheniramine 114 Citalopram 56, 134, 135, 172 Clomipramine 6, 133 CNS drug targets 39 Cocaine 41, 55, 95, 114, 151, 164, 168, 215 – dopamine transporter (DAT) 41 – reinforcing effects 112 Cocaine-abuse therapy, preclinical assessment 123 Cocaine-like subjective effects 110 Cyclobutyl analogues 198 Cyclopentadiene 143 Cyclosporine A 177 Cysteine 122 – glutathione 213 Cystine 188 Cystine/glutamate exchanger 208 DAT 155 Daunorubicin, ABCB1 transporter 37 Desimipramine 165 Desipramine 7, 133 1,4-Dialkylpiperazines 97 Diaminopropionate, amide derivatives 197 Dicarboxylate/amino acid:cation (Na+ /H+ ) symporter (DAACS/SLC1) family 5, 34, 44 Difluoropine 106 Dihydro-1H-quinolin-2-ones 88 Dihydrotetrabenazine, tracer for VMAT2 174 Dihyrokainate (DHK) 199 Dipeptide transporters 45 Diphosphate bond hydrolysis-driven transporters 21 Dopamine 55 Dopamine transporters (DATs) 8, 57, 95, 137, 157, 168 – ligands 171 Dopamine uptake inhibitors 95, 131 Dothiepin 133 DOV 102677 138 DOV 216303 138 DOV 21947 138 Doxepin 133 Drug discovery 15 Drug targets 15 Drug/metabolite transporter (DMT) superfamily 32 Drug:H+ antiporter-1 (DHA1) (12 spanner) family 43 Drug–drug interactions, P-gp 3 Drug-resistance pump 31 Dual-reuptake inhibitors 53 Dual-uptake inhibitors 134 Duloxetine 3, 55, 136, 142, 147 – analogues 72 Electron microscopy 27 Electrophilic-responsive elements (EpRE) 213 E-MeP 19 Escitalopram 134, 135 Excitatory amino acid transporters (EAATs) 44, 187, 190 Facilitated diffusion 22 Facilitator superfamily 3 Fluorodeoxyglucose (FDG) 179 Fluoropaclitaxel, tracer for Pgp 178 Fluoxetine (Prozac) 3, 56, 60, 134, 171, 231 Fluvoxamine 134, 135 Furifosmine 175 GABA transporters (GAT) 24, 42 Gallium radionuclides 176 GBR 129009 98 GBR 13069 97 Generalized anxiety disorder (GAD) 151 GLAST 191, 207 Glioblastoma multiforme 214 Glucose transporters (GLUTs) 10, 22, 179 Glutamate 188 – analogues, substituted 196 – receptors 10 – transport 188 – transporter homologue, Pyrococcus horikoshii 192 – transporters 44 Glutamate/cystine exchanger 187 Glutamate dehydrogenase (GDH) 212 Glutamine synthetase 190
Subject Index 251 Glutathione (GSH) 208, 213 Glycine-N-methyltransferase 230 Glycine transporter inhibitors 223 – medicinal chemistry 229 Glycine transporter isoforms 224 Glycine transporters, membrane topology 225 GlyT1 10, 223 – inhibitors, amino acid-derived 230 – – non-amino acid-derived 235 GlyT2 10, 223 – inhibitors 240 High-throughput screening (HTS) 5 Histamine antagonists 114 Homomazindol analogues 151 Homotryptamines, substituted 59 β-threo-Hydroxyaspartate (β-THA) 194 Hydroxy-reboxetine analogues 82 Ibotenate 210, 212 Imipramine 132, 133 Indatraline 150 Lipid exporter 35 Locomotor activity, stimulation 109 Major depressive disorder (MDD) 8 Major facilitator superfamily (MFS) 2, 22, 29 Maprotiline 133 Mazindol 97, 151 McN5652 172 Membrane proteins 15 – expression/purification 25 – structures 19, 24 Membrane transporter proteins 20 Mepyramine 114 Methanethiosulfonate ethyltrimethylammonium (MTSET) 121 Methyl-D-aspartate (NMDA) receptor 224 Milnacipran 55, 136 – analogues 68 Monoamine 53, 131 – depression 132 Monoamine transporters 8 Morpholines, arylthiomethyl 81 – analogues 80 Multidrug resistance (MDR) transporters 157 – ABC transporters, cancer chemotherapy 37 – antibiotic treatment 39 – protein targets 36 Muscarinic receptor antagonist effects 115 NET 155 Neurotransmission, glutamate-mediated 189 Neurotransmitter:sodium symporter (NSS/SLC6) family 3, 32, 39 Neurotransmitters 2 Nisoxetine 165, 166 NMR spectroscopy 27 Nomifensine 136, 147 Non-competitive N-methyl-D-aspartate (NMDA) blockers 43 Noradrenaline 40, 55 Noradrenaline reuptake inhibitors (NARIs) 8, 40, 65, 80, 131, 133 Norepinephrine transporters (NETs) 57, 96, 164 Norepinephrine uptake inhibitors 132 Nortriptyline 133 NRI 53 NS-2359/GSK-372475 145 NSS transporter assays 5 Obsessive-compulsive disorder (OCD) 151 Omeprazole 21 Organic anion transporter (OAT) family 3, 29 Organic cation transporter family 3 Oxalyl-L-α,β-diaminopropionic acid (β-ODAP) 210 Paclitaxel 178 Pain 229 Parasite-encoded facilitative hexose transporter (PfHT) 22 Parkinson’s disease 98, 168, 173 Paroxetine (Paxil) 3, 56, 134, 135 Permeases 35 PET 155 – tracer/radioligand 158
252 Subject Index PET ligands, aryloxy morpholines 166 – tricyclic/bicyclic structures 166 PET tracers, modeling 161 P-glycoprotein see P-gp Pgp (MDR1/ABCB1) 2, 23, 37, 155, 157 Pgp blocker XR9576 (tariquidar) 178 Pgp expression, tumors, 67Ga/68Ga 176 Pgp inhibitors, cyclosporine A 177 Pgp tracers, fluoropaclitaxel 178 1-Phenyl-2-methylaminomethyltetralins 232 Phenylpiperazine 97, 99 Piperazines 74 Piperidines 78 Place conditioning 113 Porters 21 Positron emission tomography 155 Post-synaptic glycine receptors (GlyR) 224 PRC-025 142 PRC-050 142 Premature ejaculation (PE) 61 Primary active transporters 22 Probenecid 20 Prodrug targets 45 Propanamine analogues 72 Psychomotor stimulant drugs 109 Punishing stimulus 116 Pyran derivatives, substituted 148 Pyridinyl phenyl ethers 89 Pyrovalerone 97 Pyrrolidine dicarboxylate (PDC) 187 – analogues 199 Pyrrolidines 76 – 3,4-disubstituted 150 Quisqualic acid 210 Radionuclides 158 Reboxetine 40, 55, 80, 133, 165 – analogues 83 Receptor occupancy (RO) 163 Resistance-nodulation-cell division superfamily 31 Reuptake carriers, dopamine (DAT) 157 – excitatory amino acid transporters (EAATs) 157 – GABA (GAT) 157 – glycine (GLYT) 157 – norepinephrine (NET) 157 – sodium/chloride-dependent transporters for serotonin (SERT) 157 – sodium-dependent glutamic acid transporters 157 Rimcazole 98 RTI-121 169 SAR 53, 131 Sarcosine 227, 230 Schizophrenia 43, 228, 235 Scopolamine 115 Secondary active transporters 23 Selective serotonin reuptake inhibitors 8, 57, 133 SEP-225289 145 Serine-O-sulfate 212 Serotonin 54 Serotonin reuptake inhibitors 57, 65 – ligands, positron emission tomography 63 – selective 8, 57, 131, 133 – – tropane based 57, 145 Serotonin transporters (SERTs) 24, 57, 96, 100, 155, 171 Sertraline (Zoloft) 3, 56, 63, 134, 135 Sestamibi 175 Sibutramine 136, 147 Single photon emitting radionuclides (SPECT) 158 Small multidrug resistance (SMR) family 32 SNDRI 131 SNRIs 8, 53, 55, 134 Social anxiety disorder (SAD) 151 Sodium symporter family 3 Sodium-dependent neutral amino acid transporters ASCTs 191 Solute carrier family (SLC) 3, 191 SSRI 53, 55 Structure prediction, three-dimensional 28 Structure-based drug design (SBDD) 6 Subtype specificity 202 Sulfasalazine 210 Symport 3, 23 Symporters 21 Synaptic plasticity 189 Talupram/talsupram 165, 166 Tamoxetine 166
Subject Index 253 Taxanes 178 Tertiary active transporters 24 Tetracycline, resistance 39 Tetrahydropyridines 60 Tetrofosmin 175 Therapeutic potential 227 Thiadiazol-4-yl propionic acid (TDPA) 201 Thiophenylphenyl tropane 58 Thyroid hormone transporter (MCT8) 29 Tomoxetine 85 Tourette’s syndrome 168 Transport, active/passive 22 Transport classification database (TCDB) 37 Transporters 15, 19 – 3D structure 29 – ATP-binding cassette (ABC) 22 – classification 2 – drug absorption/distribution/elimination 44 – drug discovery 1, 8 – PET studies 164 – structure-based drug design (SBDD) 6 Tricyclic antidepressants (TCA) 54, 131, 132, 151 Trihexyphenidyl 115 Triple-uptake inhibitors (TUIs) 131 – design/synthesis/structure–activity 137 – Eli Lilly 143 – series 148 Tropanes 145 – constrained 79 Uniport 3 Uniporters 21 Venlafaxine 3, 55, 135 – analogues 142 Verapamil 176 Vesicular monoamine transporters (VMATs) 29, 43, 157, 173 Viloxazine analogues 84 Vincristine, ABCB1 transporter 37 X-ray crystallography 24, 26 Xenobiotics 2 ZIENT 63