Serotonin reuptake inhibitors: The cancer stone in treatment of depression for half a century - A medicinal chemistry survey

Current Topics in Medicinal Chemistry

Volumn 6, Issue 17, 2006, Pages 1801-1823

  Moltzen, Ejner K ^a   Bang Andersen, Benny ^a  

^a H LUNDBECK A S   (Denmark)

Author keywords

5 HT2A; 5 HT2C; Add on; ASRI; Augmentation; Combination; DAT; Dopamine; NET; Norepinephrine; Reuptake inhibition; Serotonin; SERT; SSRI

Indexed keywords

AMITRIPTYLINE; ARIPIPRAZOLE; CITALOPRAM; DOPAMINE TRANSPORTER; DULOXETINE; ESCITALOPRAM; FLUOXETINE; FLUVOXAMINE; FLUVOXAMINE MALEATE; MILNACIPRAN; MONOAMINE OXIDASE INHIBITOR; N [2 [4 (2 METHOXYPHENYL) 1 PIPERAZINYL]ETHYL] N (2 PYRIDYL)CYCLOHEXANECARBOXAMIDE; NORADRENALIN TRANSPORTER; NORADRENALIN UPTAKE INHIBITOR; OLANZAPINE; PAROXETINE; PINDOLOL; PLACEBO; QUETIAPINE; REBOXETINE; SEROTONIN 1A RECEPTOR; SEROTONIN TRANSPORTER; SEROTONIN UPTAKE INHIBITOR; SERTRALINE; SIBUTRAMINE; SYMBIAX; TRICYCLIC ANTIDEPRESSANT AGENT; UNINDEXED DRUG; VENLAFAXINE; ZIMELDINE; ZIPRASIDONE;

ANTICHOLINERGIC SYNDROME; CARDIOVASCULAR DISEASE; CLINICAL CHEMISTRY; CLINICAL TRIAL; DEPRESSION; DRUG BINDING SITE; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG INDICATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG TARGETING; GENE TARGETING; HUMAN; INSOMNIA; NAUSEA; REVIEW; SEROTONIN UPTAKE; SEXUAL DYSFUNCTION; SLEEP DISORDER; STRUCTURE ANALYSIS; XEROSTOMIA;

ANTIDEPRESSIVE AGENTS; DEPRESSION; HUMANS; MOLECULAR STRUCTURE; SEROTONIN UPTAKE INHIBITORS;

EID: 33748659877     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802606778249810     Document Type: Review

References (231)

1. Spinks, D.; Spinks, G. Serotonin reuptake inhibition: an update on current research strategies. Curr. Med. Chem. 2002, 9, 799-810.
2. Schildkraut, J. J. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 1965, 122, 509-522.
3. Carlsson, A.; Lindqvist, M. Effects of antidepressant agents on the synthesis of brain monoamines. J. Neural. Transm. 1978, 43, 73-91.
4. Wong, D. T.; Hom, J. S.; Bymaster, F. P.; Hauser, K. L.; Molloy, B. B. A. Selective inhibitor of serotonin uptake: Lilly 110140, 3-(ptrifluomethylphenoxy) -N-methyl-3-phenylpropylamine. Life Sci. 1974, 15, 471-479.
5. For a historical account on the discovery of fluoxetine see: Wong, D. T.; Perry, K. W.; Bymaster, F. P. Nat. Rev. Drug Discov. 2005, 4, 764-775.
6. Charney, D. S.; Grothe, D. R.; Smith, S. L.; Brady, K. T.; Kaltsounis-Puckett, J.; Wright, C. W.; Laird, L. K.; Rush, A. J. Overview of psychiatric disorders and the role of newer antidepressants. J. Clin. Psychiatry 2002, 63 (Suppl 1), 3-9.
7. Baghai, T. C.; Moller, H. J.; Rupprecht, R. Recent progress in pharmacological and non-pharmacological treatment options of major depression. Curr. Pharm. Des. 2006, 12, 503-515.
8. Bosker, F. J.; Westerink, B. H.; Cremers, T. I.; Gerrits, M.; van der Hart, M. G.; Kuipers, S. D.; van der Pompe, G.; ter Horst, G. J.; Den Boer, J. A.; Korf, J. Future antidepressants: what is in the pipeline and what is missing? CNS Drugs 2004, 18, 705-732.
9. Costa e Silva, J.A. From restoration of neuroplasticity to the treatment of depression: Clinical experience. Eur. Neuropsychopharmacol. 2004, 14 (Suppl 5), S511-S521.
10. Adell, A.; Castro, E.; Celada, P.; Bortolozzi, A.; Pazos, A.; Artigas, F. Strategies for producing faster acting antidepressants. Drug Discov. Today 2005, 10, 578-585.
11. Bymaster, F. P., McNamara, R. K.; Tran, P. V. New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opin. Investig. Drugs 2003, 12, 531-543.
12. Vaswani, M.; Linda, F. K.; Ramesh, S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog. Neuropsychopharmacol. Biol. Psychiatry 2003, 27, 85-102.
13. Sonawalla, S. B; Fava, M. Severe depression: is there a best approach? CNS Drugs 2001, 15, 765-776.
14. Stahl, S. M. Not so selective serotonin reuptake inhibitors. J. Clin. Psychiatry 1998, 59, 343-344.
15. Owens, M. J.; Knight, D. L.; Nemeroff, C. B. Second-generation SSRIs: human monoamine transporter binding profile of Escitalopram and R-fluoxetine. Biol. Psychiatry 2001, 50, 345-350.
16. Sanchez, C.; Bøogesøo, K. P.; Ebert, B.; Reines, E. H.; Braestrup, C. Escitalopram versus Citalopram: the surprising role of the R-enantiomer. Psychopharmacology (Berl.) 2004, 174, 163-176.
17. Koch, S.: Perry, K. W.; Nelson, D. L.; Conway, R. G.; Threlkeld, P. G.; Bymaster, F. P. R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: an in vivo microdialysis and receptor binding study. Neuropsychopharmacolgy 2002, 27, 949-959.
18. Hyttel, J.; Bøogesøo, K. P.; Perregaard, J.; Sanchez, C., The pharmacological effect of Citalopram residues in the (S)-(+)- enantiomer. J. Neural Transm. Gen. Sect. 1992, 88, 157-160.
19. Rausch, J. L.; Corley, K. M.; Hobby, H. M. Improved potency of escitalopram on the human serotonin transporter: demonstration of an ex vivo assay technique. J. Clin. Psychopharmacol. 2004, 24, 209-213.
20. Sanchez, C.; Bergqvist, P. B.; Brennum, L. T.; Gupta, S.; Hogg, S.; Larsen, A.; Wiborg, O. Escitalopram, the S-(+)-enantiomer of Citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl.) 2003, 167, 353-362.
21. Larsen, A. K.; Brennum, L. T.; Egebjerg, J.; Sanchez, C.; Halldin, C.; Andersen, P. H. Selectivity of [3H]-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo to mice; correlation with behavioural effects. Br. J. Pharmacol, 2004, 141, 1015-1023.
22. Kasper, S. Unique mechanism of action for escitalopram: does it hold the promise? Int. J. Psychiatry Clin. Practice 2004, 8, 15-18.
23. Thase, M. E. Managing depressive and anxiety disorders with escitalopram. Expert Opin. Pharmacother. 2006, 7, 429-440.
24. Montgomery, S. A.; Loft H.; Sanchez, C.; Reines, E. H.; Papp, M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol. Toxicol. 2001, 88, 282-286.
25. Møork, A.; Kreilgaard, M.; Sanchez, C. The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 2003, 45, 167-173.
26. Storustovu, S.; Sanchez, C.; Pörzgen, P.; Brennum, L. T.; Larsen, A. K.; Pulis, M.; Ebert, B. R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Br. J. Pharmacol. 2004, 142, 172-180.
27. Sanchez, C.; Kreilgaard, M. R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram. Pharmacol. Biochem. Behav. 2004, 77, 391-398.
28. El Mansari M.; Sanchez, C.; Chouvet, G.; Renaud, B.; Haddjeri, N. Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology 2005, 30, 1269-1277.
29. Sanchez, C.; Gruca, P.; Bien, E.; Papp, M. R-citalopram counteracts the effect of escitaloprarm in a rat conditioned fear stress model of anxiety. Pharmacol. Biochem. Behav. 2003, 75, 903-907.
30. Sanchez, C.; Gruca, P.; Papp, M. R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model. Behav. Pharmacol. 2003, 14, 465-470.
31. Sanchez, C. R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model. Eur. J. Pharmacol. 2003, 464, 155-158.
32. Bræstrup, C.; Sanchez, C. Escitalopram: a unique mechanism of action. Int. J. Psychiatry Clin. Practice 2004, 8, 11-13.
33. Mnie-Filali, O.; Mansari, M. E.; Espana, A.; Sanchez, C.; Haddjeri, N. Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci. Lett. 2006, 395, 23-27.
34. 3H]citalopram binding to the 5-HT transporter from brain and platelets. Eur. J. Pharmacol. 1991, 206, 243-250.
35. Nandi, A.; Dersch, C. M.; Kulshrestha, M.; Ananthan, S.; Rothman, R. B. Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter. Synapse, 2004, 53, 176-183.
36. 3H-S-citalopram with the human serotonin transporter by an allosteric mechanism. Eur. Neuropsychopharmacol. 2003, 13, S217.
37. Chen, F.; Larsen, M. B.; Neubauer, H. A.; Sanchez, C.; Plenge, P.; Wiborg, O. Characterization of an allosteric citalopram-binding site at the serotonin transporter. J. Neurochem. 2005, 92, 21-28.
38. Chen, F.; Larsen, M. B.; Sanchez, C.; Wiborg O. The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur. Neauropsychopharmacol. 2005, 15, 193-198.
39. Montgomery, S. A. Escitalopram and depression. CMG Books. Pocket Pharma, 2002.
40. Nøorregaard, L.; Gether, U. The monoamine neurotransmitter transporters: structure, conformational changes and molecular gating. Curr. Opin. Drug Discov. Devel. 2001, 4, 591-601.
41. Ravna, A. W.; Sylte, I.; Dahl, S. G. Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters. J. Pharmacol. Exp. Ther. 2003, 307, 34-41.
42. Ravna, A. W.; Sylte, I., Kristiansen, K.; Dahl, S. G. Putative drug binding conformations of monoamine transporters. Bioorg. Med. Chem. 2006, 14, 666-675.
43. +/Cl-dependent neurotransmitter transporters. Nature 2005, 437, 215-223.
44. Henry, L. K.; Defelice, L. J.; Blakely, R.D. Getting the message across: a recent transporter structure shows the way. Neuron 2006, 49, 791-796.
45. Plenge, P.; Wiborg, O. High- and low-affinity binding of S-citalopram to the human serotonin transporter mutated at 20 putatively important amino acid positions. Neurosci. Lett. 2005, 383, 203-208.
46. Neubauer, H. A.; Hansen, C. G.; Wiborg, O. Dissection of an allosteric mechanism on the serotonin transporter: a cross-species study. Mol. Pharmacol. 2006, 69, 1242-1250.
47. Shelton, R. C. The use of antidepressants in novel combination therapies. J. Clin. Psychiatry 2003, 64 (Suppl 2), 14-18.
48. Artigas, F.; Perez, V.; Alvarez, E. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch. Gen. Psychiatry 1994, 51, 248-251.
49. Brunello, N.; Mendlewicz, J.; Kasper, S.; Leonard, B.; Montgomery, S.; Nelson, J.; Paykel, E.; Versiani, M.; Racagni, G. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur. Neuropsychopharmacol. 2002, 12, 461-475.
50. Humble, M. Noradrenaline and serotonin reuptake inhibition as clinical principles: a review of antidepressant efficacy. Acta Psychiatr. Scand Suppl. 2000, 402, 28-36.
51. Lambert, O.; Bourin, M. SNRIs: Mechanism of action and clinical features. Expert Review of Neurotherapeutics 2002, 2, 849-858.
52. Lecrubier, Y. Milnacipran: The clinical properties of a selective serotonin and noradrenaline reuptake inhibitor (SNRI). Hum. Psychopharmacol. 1997, 12, S127-S134.
53. Zajecka, J. M.; Albano, D. SNRIs in the management of acute major depressive disorder. J. Clin. Psychiatry 2004, 65 (Suppl, 17), 11-18.
54. Karpa, K. D.; Cavanaugh, J. E.; Lakoski, J. M. Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev. 2002, 8, 361-376.
55. Bymaster, F. P.; Beedle, E. E.; Findlay, J.; Gallagher, P. T.; Krushinski, J. H.; Mitchell, S.; Robertson, D. W.; Thompson, D. C.; Wallace, L.; Wong, D. T. Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake. Bioorg. Med. Chem. Lett. 2003, 13, 4477-4480.
56. Ryan, D. H. Clinical use of sibutramine. Drugs Today (Barc) 2004, 40, 41-54.
57. Wernicke, J. F.; Gahimer, J.; Yalcin, I.; Wulster-Radcliffe, M.; Viktrup, L. Safety and adverse event profile of duloxetine. Expert Opin. Drug Saf. 2005, 4, 987-993.
58. Boot, J. R.; Brace, G.; Delatour, C. L.; Dezutter, N.; Fairhurst, J.; Findlay, J.; Gallagher, P. T.; Hoes, I.; Mahadevan, S.; Mitchell, S. N.; Rathmell, R. E.; Richards, S. J.; Simmonds, R. G.; Wallace, L.; Whatton, M. A. Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake. Bioorg. Med. Chem. Lett. 2004, 14, 5395-5399.
59. Boot, J. R.; Boulet, S. L.; Clark, B. P.; Cases-Thomas, M. J.; Delhaye, L.; Diker, K.; Fairhurst, J.; Findlay, J.; Gallagher, P. T.; Gilmore, J.; Harris, J. R.; Masters, J. J.; Mitchell, S. N.; Naik, M.; Simmonds, R. G.; Smith, S. M.; Richards, S. J.; Timms, G. H.; Whatton, M. A.; Wolfe, C. N.; Wood, V. A. N-Alkyl-N-arylmethylpiperidin-4-amines: Novel dual inhibitors of serotonin and norepinephrine reuptake. Bioorg. Med. Chem. Lett. 2006, 16, 2714-2718.
60. Millan, M. J.; Gobert, A.; Lejeune, F.; Newman-Tancredi, A.; Rivet, J. M.; Auclair, A.; Peglion, J. L. S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J. Pharmacol. Exp. Ther. 2001, 298, 565-580.
61. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor. Eur. J. Pharmacol. 2003, 461, 99-104.
62. 1A antagonists. Trends Neurosci. 1996, 19, 378-383.
63. Artigas, F.; Celada, P.; Laruelle, M.; Adell, A. How does pindolol improve antidepressant action? Trends Pharmacol. Sci. 2001, 22, 224-228.
64. Ballesteros, J.; Callado, L. F. Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J. Affect. Disord. 2004, 79, 137-147.
65. Martinez, D.; Broft, A.; Laruelle, M. Pindolol augmentation of antidepressant treatment: recent contributions from brain imaging studies. Biol. Psychiatry 2000, 48, 844-853.
66. Neumeister, A.; Young, T.; Stastny, J. Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter. Psychopharmacology (Berl.) 2004, 174, 512-524.
67. Cummings, P. J.; Tulloch, I. F. A formulation comprising selective serotonin re-uptake inhibitors in quick-release form and beta-blockers in sustained release form. WO 9902142. 1999.
68. Depoortere, H. Treating depression with a combination of fluoxetine, pindolol and buspirone. WO 0006160. 2000.
69. 1A receptor antagonist to potentiate the action of a 5-HT reuptake inhibitor in the treatment of sleep disorders. US 5776969. 1998.
70. James, S. P. Treatment of sleep disorders. EP 792649. 1997.
71. Artigas Perez, F. Potentiation of drug response by increasing serotonin availability. EP 818198. 1998.
72. 1B antagonist or partial agonist, for the treatment of affective disorders. WO 9913877. 1999.
73. 1A antagonist WO 9633710. 1996.
74. Howard, H. R. Novel lactam derivatives are 5-HT ligands. WO 9736867. 1997.
75. Chenard, B. L.; Desai, K. A.; Howard, H. R.; Macor, J. E.; Shenk, K. D. Aryl and heteroaryl alkoxynaphthalene derivatives. WO 9600720. 1996.
76. Macor, J. E. 4-Indole derivatives as serotonin agonists and antagonists. WO 9603400. 1996.
77. 1A receptor antagonism/SSRI activities. Part 1. Bioorg. Med. Chem. Lett. 2003, 13, 1903-1905.
78. 1A receptor antagonism/SSRI activities. Part 2. Bioorg. Med. Chem. Lett. 2003, 13, 2393-2397.
79. 1A receptor antagonism/SSRI activities. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 3939-3942.
80. 1A receptor antagonism/SSRI activities. Part 4. Bioorg. Med. Chem. Lett. 2004, 14, 2653-2656.
81. 1A receptor antagonism/SSRI activities. Part 5. Bioorg. Med. Chem. Lett. 2006, 16, 2347-2351.
82. Kohlman, D. T.; Liang, S. X.; Xu, Y.-C. Piperidine derivatives as serotonin reuptake inhibitors. WO 0123381. 2001.
83. Liang, S. X.; Xu, Y.-C. Piperidine derivatives as serotonin reuptake inhibitors. WO 0123380. 2001.
84. Hertel, L. W.; Xu, Y.-C. Novel pyrrolidine and pyrroline derivatives having effects on serotonin-related systems. WO 0000196. 2000.
85. Hertel, L. W.M.; Kohlmam, D. T.; Liang, S. X.; Wong, D. T.; Xu, Y.-C. Novel piperidine derivatives having effects on serotonin-related systems. WO 0000198. 2000.
86. Hauser, K. L.; Hertel, L. W.; Xu, Y.-C. Novel azepine derivatives having effects on serotonin-related systems. WO 0000203. 2000.
87. 1A/2A receptor antagonist. In: Serotonin: From Molecule to Clinic. New Orleans, US, 2000, The Serotonin Club.
88. Threlkeld, P. G.; Xu, Y. C.; Bymaster, F. P.; Shaw, J. L.; Wong, D. T.; Dreshfield-Ahmad, L. J. Ex vivo and in vivo pharmacology of LY433221, a combined serotonin (5-HT) reuptake inhibitor and 5-HT1A/2A receptor antagonist. In: Serotonin: From Molecule to Clinic. New Orleans, US, 2000, The Serotonin Club.
89. 1A/2A receptor antagonist. In: Serotonin: From Molecule to Clinic. New Orleans, US, 2000, The Serotonin Club.
90. 1A/2A receptor antagonist. In: Serotonin: From Molecule to Clinic. New Orleans, US, 2000, The Serotonin Club.
91. 1A receptor antagonists with potent 5-HT reuptake inhibitory activity. Bioorg. Med. Chem. Lett. 2005, 15, 737-741.
92. Meagher, K. L.; Mewshaw, R. E.; Evrard, D. A.; Zhou, P.; Smith D. L.; Scerni, R.; Spangler, T.; Abulhawa, S.; Shi, X.; Schechter, L. E.; Andree, T. H. Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors. Bioorg. Med. Chem. Lett. 2001, 11, 1885-1888.
93. 1A antagonist component into a class of serotonin reuptake inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 307-310.
94. 1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines. J. Med. Chem. 2004, 47, 3823-3842.
95. 1A receptor. Bioorg. Med. Chem. Lett. 2005, 15, 911-914.
96. 1A receptor and serotonin transporter affinity. Bioorg. Med. Chem. Lett. 2006, 16, 1338-1341.
97. Tran, M.; Stack, G. P. Antidepressant heterocyclylmethyl derivatives of 2,3-dihydro-1,4-dioxino(2,3-f)quinoline. WO 02072587. 2002.
98. 1A activity and putative fast onset of antidepressant action. 18th International Symposium on Medicinal Chemistry, 2004 (Poster 196). 2004. Copenhagen, Denmark.
99. 1A activity and putative fast onset of antidepressant action. Society for Neuroscience, 33rd Annual Meeting, 2003 (Poster 958.17). 2003. New Orleans, USA.
100. Dimitriou, E. C.; Dimitriou, C. E. Buspirone augmentation of antidepressant therapy. J. Clin. Psychopharmacol. 1998, 18, 465-469.
101. 1A serotonin receptors and serotonin transporter as a new class of antidepressants. Eur. J. Med. Chem. 2001, 36, 55-61.
102. 1A receptors. J. Med. Chem. 2002, 45, 4128-4139.
103. 1A serotonin receptors and serotonin transporter, as a new class of antidepressants. J. Med. Chem. 2001, 44, 418-428.
104. 1A receptor agonist. Neuropsychopharmacology 2003, 28, 445-456.
105. 1A receptors. Eur. J. Pharynacol. 2002, 442, 63-71.
106. 1A receptor agonists and serotonin reuptake inhibitors. J. Med. Chem. 2004, 47, 4684-4692.
107. 1A receptor partial agonist /serotonin reuptake inhibitor, vilazodone. Eur. J. Pharmacol. 2005, 510, 49-57.
108. 1A agonists and 5-HT reuptake inhibitors by combination of indole-butyl-amine and chromenonyl-piperazine structural elements in a single molecular entity. Bioorg. Med. Chem. 2004, 12, 4843-4852.
109. Thase, M. E. What role do atypical antipsychotic drugs have in treatment-resistant depression? J. Clin. Psychiatry 2002, 63, 95-103.
110. Walsh, K. H.; McDougle, C. J. Pharmacological augmentation strategies for treatment-resistant obsessive-compulsive disorder. Expert Opin. Pharmacother. 2004, 5, 2059-2067.
111. Robertson, M. M.; Trimble, M. R. Major tranquillisers used as antidepressants. A review. J. Affect. Disord. 1982, 4, 173-193.
112. Ostroff, R. B.; Nelson, J. C. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J. Clin. Psychiatry 1999, 60, 256-259.
113. Hirose, S.; Ashby, C. R., Jr. An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. J. Clin. Psychiatry 2002, 63, 733-736.
114. Shelton, R. C.; Tollefson, G. D.; Tohen, M.; Stahl, S.; Gannon, K. S.; Jacobs, T. G.; Buras, W. R.; Bymaster, F. P.; Zhang, W.; Spencer, K. A.; Feldman, P. D.; Meltzer, H. Y. A novel augmentation strategy for treating resistant major depression. Am. J. Psychiatry, 2001, 158, 131-134.
115. Shelton, R. C.; Williamson, D. J.; Corya, S. A.; Sanger, T. M.; Van Campen, L. E.; Case, M.; Briggs, S. D.; Tollefson, G. D. Olanzapine/ fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J. Clin. Psychiatry 2005, 66, 1289-1297.
116. Devarajan, S.; Dursun, S. M. Olanzapine plus venlafaxine in treatment-resistant depression. J. Psychopharmacol 2005, 19, 434-435.
117. Papakostas; G. I., Petersen, T. J.; Nierenberg, A. A.; Murakami, J. L.; Alpert, J. E.; Rosenbaum, J. F.; Fava, M. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J. Clin. Psychiatry 2004, 65, 217-221.
118. Papakostas, G. I.; Petersen, T. J.; Kinrys, G.; Burns, A. M.; Worthington, J. J.; Alpert, J. E.; Fava, M.; Nierenberg, A. A. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J. Clin. Psychiatry 2005, 66, 1326-1330.
119. Simon, J. S.; Nemeroff, C. B. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J. Clin. Psychiatry 2005, 66, 1216-1220.
120. Devarajan, S.; Ali, J.; Dursun, S. M. Quetiapine plus SSRI in treatment-resistant depression: possible mechanisms. Psychopharmacology (Berl.) 2006, 185, 402-403.
121. Denys, D.; van Megen, H.; Westenberg, H. Quetiapine addition to serotonin reuptake inhibitor treatment in patients with treatment-refractory obsessive-compulsive disorder: an open-label study. J. Clin. Psychiatry 2002, 63, 700-703.
122. Adson, D. E.; Kushner, M. G.; Eiben, K. M.; Schulz, S. C. Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress. Anxiety 2004, 19, 121-126.
123. Shelton, R. C. The combination of olanzapine and fluoxetine in mood disorders. Expert Opin. Pharmacother. 2003, 4, 1175-1183.
124. Shelton, R. C.; Stahl, S. M. Risperidone and paroxetine given singly and in combination for bipolar depression. J. Clin. Psychiatry 2004, 65, 1715-1719.
125. Seemuller, F.; Forsthoff, A.; Dittmann, S.; Born, C.; Bernhard, B.; Severus, W. E.; Grunze, H. The safety and tolerability of atypical antipsychotics in bipolar disorder. Expert Opin. Drug. Saf. 2005, 4, 849-868.
126. de Boer, T. The pharmacologic profile of minazapine. J. Clin. Psychiatry 1996, 57, Suppl 4, 19-25.
127. Wan, D. D.; Kundhur, D.; Solomons, K.; Yatham, L. N.; Lam, R. W. Mirtazapine for treatment-resistant depression: a preliminary report J. Psychiatry Neurasci. 2003, 28, 55-59.
128. Rojo, J. E.; Ros, S.; Aguera, L.; de la, Gandara J.; de Pedro, J. M. Combined antidepressants: clinical experience. Acta Psychiatr. Scand. Suppl. 2005, 25-31, 36.
129. 2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 2005, 30, 2205-2215.
130. 2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychoparmacology 2003, 28, 402-412.
131. Zhang, W.; Perry, K. W.; Wong, D. T.; Potts, B. D.; Bao, J., Tollefson; G. D.; Bymaster, F. P. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 2000, 23, 250-262.
132. Huang, M.; Ichiwaka, J.; Li, Z.; Dai, J.; Meltzer, H. Y. Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex. Psychopharmacology (Berl.) 2006, 185, 274-281.
133. 2A receptors in depression. J. Psychiatry Neurosci. 2004, 29, 252-265.
134. Davis, R.; Whittington, R.; Bryson, H. M. Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 1997, 53, 608-636.
135. Eison, A. S.; Eison, M. S.; Torrente, J. R.; Wright, R. N.; Yocca, F. D. Nefazodone: preclinical pharmacology of a new antidepressant. Psychopharmacol. Bull. 1990, 26, 311-315.
136. Hemrick-Luecke, S. K.; Snoddy, H. D.; Fuller, R. W. Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo. Life Sci. 1994, 55, 479-483.
137. 18F]-setoperone PET. Psychopharmacology (Berl.) 1999, 144, 279-281.
138. 35S]GTPγS binding. J Psychopharmacol. 2005, 19, 235-241.
139. 2A receptor antagonistic activity. Neuropharmacology 1996, 35, 1621-1626.
140. Pullar, I. A.; Carney, S. L.; Colvin, E. M.; Lucaites, V. L.; Nelson, D. L.; Wedley, S. LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone. Eur. J. Pharmacol. 2000, 407, 39-46.
141. 2C receptors in affective disorders. Expert Opin. Investig. Drugs 1998, 7, 1587-1599.
142. 2C agonists as potential antidepressants. IDrugs 1999, 2, 109-120.
143. Wood, M. D.; Thomas, D. R.; Watson, J. M. Therapeutic potential of serotonin antagonists in depressive disorders. Expert Opin. Investig. Drugs 2002, 11, 457-467.
144. 2C receptor antagonists: a new approach to the treatment of depression and anxiety. In: Medicinal Chemistry. 2nd ed, King, F. D., Ed.; Royal Society of Chemistry, Cambridge, UK, 2002; 382-396.
145. 2C receptor antagonists in the treatment of anxiety disorders. Curr. Drug Targets. CNS Neurol. Disord. 2003, 2, 383-387.
146. 2C receptor as a target for mood disorders. Expert Opin. Ther. Targets 2004, 8, 15-23.
147. 2C receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 2004, 29, 1782-1789.
148. Kehler, J.; Kroll, F.; Juhl, K. 2-(1H-Indolsulfanyl)arylamine derivatives and their preparation, pharmaceutical compositions, and use as serotonin, norepinephrine, and dopamine reuptake inhibitors in the treatment of affective disorders, pain, ADHD and stress urinary incontinence. WO 2006007843. 2006.
149. Baxter, A. D.; Walmsley, A.; Lasterra, E. Novel benzoxazocines and their preparation, pharmaceutical composition, and therapeutic use as noradrenaline and serotonin reuptake inhibitors for treatment of pain and emesis. US 2006019940. 2006.
150. Bish, G.; Brown, A. D.; Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Preparation of piperazine derivatives which exhibit activity as serotonin and noradrenaline reuptake inhibitors. WO 2005068447. 2005.
151. Clark, B. P.; Cases-Thomas, M. J.; Gallagher, P. T.; Gilmore, J.; Masters, J. J.; Timms, G. H.; Whatton, M. A.; Wood, M. Preparation of N,N-disubstituted 4-aminopiperidines as inhibitors of monoamine, in particular serotonin, norepinephrine, and dopamine reuptake. WO 2004052858. 2004.
152. Boulet, S. L.; Clark, B. P.; Fairhurst, J.; Gallagher, P. T.; Johansson, A. M.; Whatton, M. A.; Wood, M. Preparation of 4-aminopiperidine derivatives as monoamine uptake inhibitors. WO 2005092885. 2005.
153. Boulet, S. L.; Filla, S. A.; Gallagher, P. T.; Hudziak, K. J.; Johansson, A. M.; Karanjawala, R. E.; Whatton, M. A.; Masters, J. J.; Matassa, V.; Mathes, B. M.; Rathmell, R. E.; Wolfe, C. N. Preparation of 3-aryloxy/thio-2,3-substituted propanamines and their use in inhibiting serotonin and norepinephrine reuptake. WO 2004043904. 2004.
154. Boulet, S. L.; Filla, S. A.; Gallagher, P. T.; Hudziak, K. J.; Johansson, A. M.; Karanjawala, R. E.; Masters, J. J.; Matassa, V.; Mathes, B. M.; Rathmell, R. E.; Whatton, M. A.; Wolfe, C. N. Preparation of 3-aryloxy/thio-2,3-substituted propanamines and their use in inhibiting serotonin and norepinephrine reuptake. WO 2004043903. 2004.
155. Bøgesø, K. P.; Pueschl, A.; Kehler, J.; Bregnedal, P. Preparation of aminoindane derivatives as serotonin and norepinephrine uptake inhibitors. WO 03055873. 2003.
156. Beck, J. P.; Curry, M. A.; Smith, M. A. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin. WO 01032625. 2001.
157. Molino, B. F.; Liu, S.; Berkowitz, B. A.; Guzzo, P. R.; Beck, J. P.; Cohen, M. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and their preparation, pharmaceutical compositions and use thereof to block reuptake of norepinephrine, dopamine, and serotonin for the treatment of neurological and psychological disorders. WO 2006020049. 2006.
158. Kodo, T.; Yagi, H.; Dan, A.; Masumoto, S.; Kinomura, N.; Koyama, K. Novel cyclic amines useful as 5-HT reuptake inhibitors in the treatment of neurological diseases. WO 03053928. 2003.
159. Nishiyama, A.; Bougauchi, M.; Minoguchi, M.; Morio, Y.; Kuroita, T. Kanzaki, K. Novel phenoxypropylamino compounds useful in the treatment of depression. WO 0071517. 2000.
160. 1A antagonists and as serotonin reabsorption inhibitors. WO 9823586. 1998.
161. Mewshaw, R. E.; Shah, U. S. Novel 3,4-dihydro-2H-benzo(1,4)oxazine derivatives and their use in the treatment of depression. WO 0040581. 2000.
162. Mewshaw, R. E.; Meagher, K. L. Tetrahydroisoquinolinyl-alkylindole derivatives useful for the treatment of depression. WO 0064884. 2000.
163. Mewshaw, R. E.; Zhou, P.; Zhou, D.; Meagher, K. L.; Asselin, M.; Evrard, D. A.; Gilbert, A. M. Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression. WO 0040554. 2000.
164. Mewshaw, R. E.; Baudy, R. B. Novel 1,4-disubstituted cyclohexane derivatives for the treatment of depression. WO 0040579. 2000.
165. Mewshaw, R. E.; Zhou, D.; Zhou, P. Novel 3,4-dihydro-2H-benzo (1,4)-oxazinylmethyl-(3-(1H-indol-3-yl)-alkyl)amines and their use for the treatment of depression. WO 0040580. 2000.
166. Mewshaw, R. E.; Zhou, D. N-aryloxyethyl-indolyl-alkylamines for the treatment of depression. WO 9951575. 1999.
167. Mewshaw, R. E.; Zhou, P. Novel indol-3-yl-cyclohexylamines which are useful for the treatment of depression. WO 9951592. 1999.
168. Mewshaw, R. E.; Nelson, J. A. N-aryloxyethyl-indolyl-alkylamines for the treatment of depression. WO 9951591. 1999.
169. Mewshaw, R. E.; Zhou, D.; Zhou, P. N-aryloxyethylamine derivatives for the treatment of depression. WO 9951576. 1999.
170. Lubisch, W.; Dullweber, U.; Starck D.; Steiner, G.; Bach, A.; Emling, F.; Garcia-Ladona, X.; Teschendorf, H.-J.; Wicke, K. Antidepressant 3-substituted tetrahydropyridopyrimidinone derivatives with serotonin-modulating and serotonin-uptake inhibiting activity. WO 9921857. 1999.
171. 1D). WO 9920616. 1999.
172. Bentley, J.; Bergauer, M.; Bertani B.; Biagetti M.; Borriello, M.; Bromidge, S. M.; Gianotti, M.; Granci, E.; Leslie, C. P.; Pasquarello, A.; Zucchelli, V. Fused tricyclic derivatives for the treatment of psychotic disorders. WO 2006024517. 2006.
173. 1A receptor ligands and 5-HT uptake inhibitors useful for treating anxiety. EP 1078928. 2001.
174. Pinney, K. G.; Miranda, M. G.; Dorsey, J. M. Preparation of piperazine or piperidine derivatives as serotonin reuptake inhibitors. WO 2005094896. 2005,
175. 2 receptors antagonists and selective serotonin re-uptake inhibitors - useful for the treatment of e.g. depression, anxiety and panic disorders, dementia, mental handicap and Alzheimer's disease. WO 2005002578. 2005.
176. 2A receptor antagonists. EP 1178048. 2002.
177. Butler, T. W.; Fliri, A. F. J.; Gallaschun, R. J.; Jones, B. P.; Ragan, J. A. Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof. EP 1083178. 2001.
178. 2A ligands and as serotonin reuptake inhibitors for use in treating central nervous system disorders. WO 9958525, 1999.
179. Fairhurst, J. Benzothiadiazinyl-indole derivatives and their use as serotonin receptor ligands. WO 9910346. 1999.
180. 2A receptor ligands and inhibitors of 5-HT reuptake. US 5929072. 1999.
181. 2A antagonistic activity and their use for treating diseases of the central nervous system. WO 9838189, 1998.
182. Perregaard, J. K.; Stenberg, J. W.; Hansen, B. 4-Aryl-l-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzo-thiophenemethyl) piperidines, tetrahydropyridines or piperazines. WO 9533721. 1995.
183. Püschl, A.; Bang-Andersen, B.; Jørgensen, M.; Juhl, K.; Ruhland, T.; Andersen, K.; Kehler, J. 4-(2-Phenoxyphenyl)-1,2,3,6-tetrahydropyridine derivatives are serotonin reuptake inhibitors - useful for the treatment of affective disorders. WO 2004087662. 2004.
184. 2c receptor modulators - useful for treating e.g. depression and anxiety disorders. WO 2004087156. 2004.
185. Ruhland, T.; Smith, G. P.; Bang-Andersen, B.; Püschl, A.; Moltzen, E. K., Andersen, K. Phenyl-piperazine derivatives as serotonin reuptake inhibitors. WO 03029232. 2003.
186. 2C antagonist, inverse agonist or partial agonist. WO 01041701. 2001.
187. Bøgesø, K. P.; Cremers, T. I. F. H. The combination of a serotonin reuptake inhibitor and irindalone for the treatment of depression and other affective disorders. WO 01041766. 2001.
188. Krishnan, R. R.; Caron, M. G.; Zhang, X. Use of a serotonin reuptake inhibitor in combination with a second active agent - for treating serotonergic neurotransmission dysregulation disorders e.g. depression, anxiety and substance abuse. WO 2005112906. 2005.
189. Cremers, T. I. F. H.; Hogg Willigers, S. The combination of a serotonin reuptake inhibitor and a histamine 3 receptor antagonist, inverse agonist or partial agonist, and therapeutic use thereof. WO 2005056056. 2005.
190. 3 receptor antagonist with a serotonin reuptake inhibitor for the treatment of depression. US 20020107244. 2002.
191. 3 antagonist in combination with a 5-HT reuptake inhibitor for the treatment of depression. WO 9959593. 1999.
192. 1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis. Bioorg. Med. Chem. Lett. 2004, 14, 2469-2472.
193. 1D antagonistic activity: a new approach toward efficient antidepressants. J. Med. Chem. 2000, 43, 1149-1157.
194. 2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response. Neuropsychopharmacolqgy 2004, 29, 1166-1171.
195. 2-antagonistic activities. J. Med. Chem. 1997, 40, 1049-1062.
196. Wu, Y-J.; He, H. New homopiperidine derivatives are modulators of tachykinins, substance P or other neurokinins and serotonin reuptake transporter protein inhibitors-useful for the treatment of depression and anxiety. US 20060019943. 2006.
197. 1/SSRI inhibitors). US 2006020019. 2006.
198. Alvaro, G.; Ghirlanda, D. Preparation of imidazol-2-ones and analogs as tachykinin antagonists and serotonin reuptake inhibitors. WO 2005121122. 2005.
199. 1 antagonists and serotonin reuptake inhibitors for treatment of depression and anxiety. WO 2005100325. 2005.
200. 1 antagonists and serotonin reuptake inhibitors. WO 2005100324. 2005.
201. 1 antagonists and selective serotonin reuptake inhibitors (SSRI). WO 2004056771. 2004.
202. Bernstein, P.; Cacciola, J.; Dedinas, R.; Shen, L.; Warwick, P. Preparation of piperidinylmethyl naphthylmethyl ethers as neurokinin 1 antagonists and serotonin reuptake inhibitors. WO 2004022539. 2004.
203. 1, receptor antagonists and serotonin reuptake inhibitors and their therapeutic uses. WO 2004020411. 2004.
204. Alvaro, G.; Cardullo, F.; D'adamo, L.; Piga, E.; Seri, C. N-benzyl-3-phenyl-3-heterocyclyl-propionamide compounds as tachykinin/ serotonin reuptake inhibitors. WO 2004005255. 2004.
205. 1 antagonists-serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 3195-3198.
206. 1 antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 2002, 12, 261-264
207. Mørk, A.; Cremers, T. I. F. H.; Willigers, S. Serotonin reuptake inhibitor combination with a GABA-B receptor antagonist for the treatment of depression and other disorders. WO 2004000326. 2004.
208. 2/3 agonist for use in anxiety and depression. EP 1254668. 2002.
209. 2/3 M agonist and a selective serotonin reuptake inhibitor. WO 9937303. 1999.
210. Chaki, S.; Oshida, Y.; Ogawa, S.; Funakoshi, T.; Shimazaki, T.; Okubo, T.; Nakazato, A.; Okuyama, S. MCL0042: A nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity. Pharmacol. Biochem. Behav. 2005, 82, 621-626.
211. Lafleur, D. L.; Pittenger, C.; Kelmendi, B.; Gardner, T.; Wasylink, S.; Malison, R. T.; Sanacora, G.; Krystal, J. H.; Coric, V. N-acetyleysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl.) 2006, 184, 254-256.
212. Krishnan, R. R.; Caron, M. G.; Zhang, X; Beaulieu, M. J.; Gainetdinov, R. R.; Raul, R. Method for augmenting the effects of serotonin reuptake inhibitors. WO 2005112906. 2005.
213. 2-agonists for the treatment of mental disorders. WO 2005067969. 2005.
214. George, T.; Sacco, K.; Vessicchio, J. Combination therapy with mecamylamine for the treatment of mood disorders. WO 2005067909. 2005.
215. Cremers, T. I. F. H.; Willigers, S. H.; Arnt, J. The combination of a serotonin reuptake inhibitor and loxapine for the treatment of depression and other affective disorders. WO 2005023243. 2005.
216. Didriksen, M.; Hogg Willigers, S.; Arnt, J. The combination of a serotonin reuptake inhibitor and a glycine transporter type 1 (GlyT-1) inhibitor for the treatment of depression, anxiety, and other affective disorders. WO 2005018676. 2005.
217. Willigers, S. The combination of a serotonin reuptake inhibitors and agomelatine for the treatment of depression and other affective disorders. WO 2005003562. 2005.
218. Migeon, J.; Revah, F. Use of alverine, alone or in combination with a tricyclic antidepressant or an antidepressant which is a specific inhibitor of serotonin reuptake, for treatment of depression. WO 2005002560. 2005.
219. Gupta, S. Combination of an NMDA receptor antagonist and a selective seratonin reuptake inhibitor for the treatment of depression and other mood disorders. WO 2005000216. 2005.
220. Sanchez, C.; Ebert, B. Gaboxadol and serotonin reuptake inhibitors for the treatment of depression and other affective disorders. WO 2004112786. 2004.
221. Harkin, A.; Connor, T. J.; Burns, M. P.; Kelly, J. P. Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur. Neuropsychopharmacol. 2004, 14, 274-281.
222. Ninan, P. T.; Hassman, H. A.; Glass, S. J.; McManus, F. C. Adjunctive modafinil at initiation of treatment with a selective setonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J. Clin. Psychiatry 2004, 65, 414-420.
223. Koyama, K.; Marumoto, S.; Toda, N.; Kogen, H.; Suzuki, K. Preparation of alkylcarbamic acid esters as acetyleholinesterase inhibitor and serotonin reuptake inhibitor. WO 02059074. 2002.
224. Howard, H. R. Jr. Combination of a serotonin reuptake inhibitor and sigma receptor ligand for the treatment of depression. EP 1224930. 2002.
225. Jenkins, S. N. Combinations of serotonin reuptake inhibitor and estrogenic agents. WO 02003975. 2002.
226. Zullino, D.; Baumann, P. Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors. Pharmacopsychiatry 2001, 34, 119-127.
227. Bauer, M. The combined use of lithium and SSRIs. Journal of Serotonin Research 1995, 2 69-76.
228. Appelberg, B. G.; Syvalahti, E. K.; Koskinen, T. E.; Mehtonen, O. P.; Muhonen, T. T.; Naukkarinen, H. H. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors:. results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J. Clin. Psychiatry 2001, 62, 448-452.
229. 4 receptor agonists, pharmaceutical compositions, and therapeutic uses. WO 2006029520. 2006.
230. Iosifescu, D. V.; Nierenberg, A. A.; Mischoulon, D.; Perlis, R. H.; Papakostas, G. I; Ryan, J. L.; Alpert, J. E.; Fava, M. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J. Clin. Psychiatry 2005, 66, 1038-1042.
231. 2C receptor ligands. EP 1023898. 2000.