- Email: [email protected]
Chapter 5. Novel Antipsychotics
Chapter 5. Novel Antipsychotlcs Harry R. Howard and Thomas F. Seeger Central Research Division Pfizer Inc Groton, CT 06340
introduction - The discovery of novel atypical antipsychotic agents with efficacy against both
positive and negative symptoms, along with a reduced side effects profile, remains a primary goal in the treatment of schizophrenia (1-3). During the past year a number of reviews have appeared which cover emerging therapies (4-6) as well as the clinical performance of more advanced candidates including remoxipride (7-9) and risperidone (10-13). Additional studies have examined agents such as bromocryptine (14), fluvoxamine (15). mianserin (16), levopromazine (17) and zotepine (18), alone or as adjunctive therapies, for control of negative symptoms or for the treatment-resistant patient.
- Further characterization of newly identified dopamine receptors (D3, D4, D5) has included the first autoradiographic visualization of D3 receptors in rat (19) and human brain (20). The D4 receptor has been found to exist as several polymorphic variants, which may explain the genetic range of susceptibility to schizophrenia and / or varied individual response to antipsychotics (21). Agents with highly selective antagonist activity for any of the newly discovered dopamine receptors have not yet been described, although antagonism of D4 receptors is of interest as a new target (22). There has also been considerable activity in the cloning and expression of dopamine receptors during the year, including work with the D l b (23), D2 (24, 25), D3 (26) and human D4 subtypes (27). Levels of mRNA for D1, 02, D3 and 05 receptors in rat brain after neuroleptic treatment have been measured (28.29). e (DAl Rec- In addition to remoxipride ( l ) ,a variety of Dq-receptor selective antagonists are reportedly under review. For example, RWJ-25730 (2)emerged as one of the most potent analogs from a series of disubslituted pyrroles (30). Two structurally similar pyrimidinylpiperazines 3 and 4 have been disclosed which show potent D2 and 5-HTla antagonism and inhibition of locomotor activity in mice (31). A benzyl substituted analog of spiperone with high 02 affinity has been proposed as a potential PET tracer for !A&? D2 receptor occupancy studies (32).
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Antagonism of doparnine D1 receptors has also been proposed as a method for the control of negative symptomatology in schizophrenia (33, 34). Among the more recently discovered D1selective antagonists are NNC-687 (6) and some compounds from a series of tricyclic derivatives, e.g., 1, which have proven active in the inhibition of conditioned avoidance response in squirrel monkeys (35,36). A series of benzophenanthridines (e.g., 8) inhibit dopamine stimulation of adenylate cyclase activity and may possess cognition enhancement properties (37).
- Clinical trials with roxindole (EMD-49,980, $), a Dp autoreceptor agonist, showed efficacy in a group of schizophrenic patients with primary negative symptoms (38, 39), whereas, results with SDZ-HDZ912 (Ip)have been less conclusive (40). Two autoreceptor agonists with selectivity for D2 receptors - PD-135222 (1L)and PD-138276 (12)- reduce amphetamine and apomorphine-inducedlocomotor activity in mice (41, 42).
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The virtues of this atypical antipsychotic continue to be extolled (43-46). Debate on the novel mechanisrn(s) of action of clozapine continues: its superior efficacy has been attributed to interactions with a variety of receptor sites in the CNS, and this list has been expanded to include 5HTlc (47), D4 (48) and glutamate (49). The syntheses of 3H- and 14C-labelledu f o r mechanistic and metabolism studies have been described (50). A PET study using showed that, within the efficaciousdose range, a 36-52% D1 receptor occupancy could be achieved versus a 38-63% level for D2 sites (51), as compared to 70-90% occupancy seen with standard agents (52). The possible mechanisms underlying the development of agranulocytosis associated with have been investigated. One proposal emphasizes a free-radical formation which may produce proteinadducts and subsequent induction of antibodies to these conjugates: the use of appropriate levels of ascorbate has been recommended for inhibition of free radical-mediatedreactions. (53). Other similar immune response mechanisms have been proposed (54-57).
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in 15-HTI Ant- The relevence of interactions of antipsychotic agents with serotoninergic receptors has been recently reviewed (58-60). In a 12-week double-blind study with treatment refractory subjects, patients receiving risperidone (14)required ten times less anti-
Chap. 5
Howard, Seeger 41.
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Parkinsonism medication than those on haloperidol (61); efficacy has also been demonstrated in patients with coexisting anxiety or depressive syndromes (62, 63). hyitrP and hyiUn, 14 is oxidized by cytochrome P4502D6 at the 9- and 7-positions of the tetrahydropyridopyrirnidinone portion of the molecule (64). Ocaperidone (R 79,598, also combines potent 5-HT2 and Dp antagonism (65, 66); preclinical data suggest that should produce less extrapyramidal side effects (EPS) (67). other benzisoxazoles which display a similar preclinical profile are the piperidine HP-873 (B) which has entered Phase 1 I clinical evaluation (68), the piperazine HRP-392 which which inhibited inhibited apomorphine-induced climbing in mice (69) and piperidine methylphenidate-induced stereotypy without producing catalepsy (70).
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The benzisothiazolylpiperazinemoiety is also a common pharmacophore in several new combined D2 / 5-HT2 antagonists. For example, CP-88,059 (19), like SM-9018 shows high affinity and selectivity for 5-HT2 vs D2 receptors in rat; at an oral dose of 40 mg 19,PET studies determined a 70% Dp occupancy in the putamen vs the 02-selective antagonist [llC]-raclopride (71). A series of analogs including also bind with high affinity to the D2 receptor and show little potential for side effects based upon the low level of catalepsy induction (72). The Dp / 5-HT2 selective antagonist, settindole (2) has been evaluated in normal subjects for safety and tolerance (73). Finally, a series of indeno[l,2-c]pyridines, from which was exemplilied, combines selective Dp and 5-HT2 antagonism to give compounds which are active in the apomorphine-inducedclimbing assay (74).
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Structurally similar to olanzepine (LY-170053,a) combines D2 and 5-HT2 antagonism with high affinity for the D1 receptor; it was tolerated in man with no evidence of agranulocytosis (75). The dibenzothiazepin lCl-204,636 displaying affinity for both D2 and 5-HT2 receptors, has demonstrated efficacy in man with insomnia, sedation and transient sinus tachycardia being the major side effects reported (76, 77). Org-5222 (25)and Org-10490 (2L) each exhibit potent antagonism of Dp and 5-HT2 receptors and are relatively free of EPS by comparison with other agents in recent clinical trials (73, 78).
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24 Some investigators have continued to evaluate serotonin antagonists which possess little or no affinity for dopamine receptors as possible neuroleptics with minimal side effects potential. MDL100,907 is among the most 5-HT2-selective antagonists, with weak affinity for D2, 5-HTla and at sites and with behavioral and etectrophysiological activities consistent with that of an atypical antipsychotic agent (79). Also claimed to be selective 5-HT2 antagonists are a number of benzimidazolones such as 29 (80).
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In a single-blind trial of neuroleptic efficacy with eight symptomatic patients, the 5-HTg-selective antagonist zacopride produced no significant improvements; almost all subjects experienced mild to moderate sedation and no significant changes in mean HVA or plasma prolactin levels were detected (81). Benzirnidazolylpiperidines, such as are claimed to be 5-HT3 and/or 5-HT4 antagonists with potential antipsychotic activity (82). BRL-46470A has been mentioned as a possible antipsychotic agent with reduced EPS potential (83).
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- The potential role of sigma (0)receptors in the etiology of psychosis has been discussed previously (see Chapter 1, this volume). Spiropiperidine analogs such as p have been claimed as among the most o-selective compounds yet reported (84). The oxime PD-128,298 (& is a I), selective Q antagonist which showed no EPS in haloperidol-sensitizedmonkeys (as),while DuP734 is selective for both CJ and 5-HT2 receptors, blocked mescaline-induced scratching and aggressive activity, and only weakly reversed APO-induced climbing, suggesting a low EPS potential (86-88). The novel CJ antagonist XJ-887 in addition to being a potent CJ and 5-HT2
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Antipsychotics
Chap. 5
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antagonist, displayed exceptional activity in the mescaline scratch assay and isolation-induced aggression model (89). Evaluation of a series of compounds related to the cyclohexane-diamine 80-737 90) demonstrated that enhanced potency and selectivity could be achieved through (91). From a series of arninoalkoxythe greater conformational flexibility of acyclic diamines like chromones. NPC-16377 was found to reverse amphetamine-induced locomotion in mice (92).
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- Inhibition of neurokinin NK1 receptors in the CNS has been been postulated as a means of regulating dopaminergic activity indirectly, thus minimizing the potential side effects associated with overt dopamine receptor blockade (93-95). The recent availahility of selective, nonpeptide antagonists such as CP-96,345 has heightened interest in this approach; the SAR surrounding 4p has been published (96, 97) and a related ether series has also been disclosed (98). Other prototypical antagonists include the NK1selective amidine RP-67580 (41, 99-102) and a series of androstano[3,2-b]pyrimido(l,2-a]benzimidazolesfrom which WIN-51708 (42)was one of the most potent h w (103). Naphthimidazolium derivatives (e.g., 4.3)have demonstrated efficacy in a rat salivation assay (104). The human NK1 receptor gene has been cloned and expressed from a human IM-9lymphocyte cell library. (105).
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Sectlon I-CNS Agents
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McCall. Ed.
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Several additional receptors have been proposed as having a potential role in the alleviation of psychotic symptoms. Cholecystokinin (CCK) receptors, upon exposure to the CCK-B selective antagonist LY-262691 produced a reduction in the number of spontaneously active A9 and A10 dopamine neurons in the rat (106). An autoradiographic study has determined an alteration in the distribution of CCK receptors in schizophrenic brain (107). Regulation of Dp receptors yia adenosine Apelective agonists has been postulated as an alternative means of control (108, 109). Partial or full agonists for the glycine "co-agonist" site on the NMDA receptor may be useful in the treatment of schizophrenia without producing excitotoxicity (110) . Glycine agonists may, however, exacerbate symptoms for some patients, and their utility needs to be more fully investigated (111). Partial benzodiazepine agonists have also been proposed as yet another means of controlling psychotic behavior (112).
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- The genetic factor in the development of schizophrenia has been further emphasized (113-116). as has the incidence of the disease due to prior exposure to viral pathogens. (117-120). The role of autoantibodies in the onset of psychosis has similarly been examined (121-124) and hypotheses related to imbalances in second messenger systems (125) and glutamate levels (126) have been advanced. . .
- A variety of studies have been directed at understanding the interaction of neuroleptics with CNS receptors utilizing PET (127-133) and MRI techniques (134-137). Molecular modelling studies, focused upon interactions between, for example, 5-HT1a, 5-HT2 and D2 receptors and their corresponding ligands, have estimated the conformational changes which may be necessary for optimal antagonism (138-140).
- A model of schizophrenia using a chronic methamphetamine intoxication protocol has been demonstrated (141). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17. 18. 19. 20. 21. 22. 23.
A. Carlsson, Clin.Neuropharmacol,, &(Suppl. l), 271A (1992). J.M. Kane, BulLMenninger Clin., f&, 62 (1992). S. Hughes, Scrip Mag., 2, 50 (1992).
M.D. Tricklebank. L.J. Bristow and P.H. Hutson, Prog. Drug Res.. 3, 299 (1992). G.P. Reynolds, Trends Pharmacol. Sci., 116, (1992). N.J. Hrib, Chem. Ind.,& 213 (1992). T. Lewander, Clin. Neuropharmacol., l5(Suppl. l), 269A (1992). D.J. King, M. Blomqvist, S.J. Cooper, M.M. Doherty. M.J. Mitchell and R.C. Montgomery, Psychopharmacology, 1pz. 175 (1992). M. Mitchell and 8. Tandberg, Drugs of Today, 28.249 (1992). R.L. Borison, A.P. Pathiraja, 6.1. Diamond and R.C. Meibach, Psychopharmacol. Bull., 28.213
u,
(1992).
A. Claus, J. Bollen, H. Decuyper, M. Eneman, M. Malfroid, J. Peuskens and S. Heylen. Acta Psychiatr. Scand., 85, 295 (1992). F. Muller-Spahn, Clin. Neuropharmacol., fi(Suppl. l ) , 90A (1992). S.L. Heylen and Y.G. Gelders, Clin. Neuropharmacol., 15 (Suppl. l), 18OA (1992). M.A. Wolf, J.M. Diener, C. Lajeunesse and C. Shriqui, Biol. Psychiat., 1166 (1992). H. Silver and A. Nassar, Biol. Psychiat.. 698 (1992). Y. Mizuki. N. Kajimura. S. Kai, M. Suetsugi and I. Ushijima, Prog. Neuropsychopharmacol.Biol. Psychiat., 16,517 (1992). S. La1 and N.P. Nair, Acta Psychiatr. Scand., &,243 (1992). C. Barnas, C.H. Stuppaeck, C. Miller, C. Haring. Sprner, B. Unterweger and W.W. Fleischhacker, Int. J. Clin. Psychopharmacol., Z,23 (1992). D. Levesque, J. Diaz, C. Pilon, M-P. Martres. B. Giros, E. Souil. D. Schott, J.-L. Morgat, J.C. Schwartz and P. Sokoloff, Proc. Natl. Acad. Sci. USA., 89, 8155 (1992). A.M. Murray, H. Ryoo and J.N. Joyce, Eur. J. Pharmacol., 222.443(1992). H.H.M. Van Tol, C.M. Wu, H . 4 . Guan, K. Ohara, J.R. Bunzow, 0. Civelli. J. Kennedy, P. Seeman. H.B. Niznik and V. Jovanovic, Nature, 35Q,149 (1992). G. Higgins. InPharma. 842. 8 (1992). M. Tlberi, K.R. Jarvie and M.G. Caron, WO 9218533 (1992).
a,
z,
Chap. 5
24. 25. 26. 27. 28. 29. 30.
Howard, Beeger 48
Antipsychotics
w,
G. Higgins, InPharma. 8 (1992). P. Seeman, H.C. Guan. 0. Civelli, H.H.M. Van Tol. R.K. Sunahara and H.B. Niznik, Eur. J. Pharmacol. Mol. Pharm.. 222. 139 (1992). 8. Giros, P. Sokoloff,J.C. Schwartz and M.P. Martres, WO 9207937 (1992). 0. Civelli and H. Van Tol. WO 9210571 (1 9921. P.R. Buckland, M.C. Odonovan and P.' McGuff in, Psychopharmacol., 479 (1992). J.H. Meadorwoodruff. A. Mansour, D.K. Grandy. S.P. Damask, 0. Civelli and S.J. Watson, Neurosci. Lett., &&. 209 (1992). M.K. Scott, M.E. Martin, D.L. DeStefano. C.L. Fedde, M.J. Kukla and D.L. Barrett. J. Med. Chem.,
m,
g,552 (1992).
48. 49. 50 51. 52.
J.R. Prous, ed., Annu. Drug Data Rep., 14.103 (1992). R.H. Mach, J.R. Jackson, R.R. Luedtke. K.J. Ivins. P.B. Molinoff and R. L. Ehrenkaufer, J. Med. Chem.,& 423 (1992). M.R. Lynch, Prog. Neuropsychopharmacol. Biol. Psychiat., 16,797 (1992). S.A. Daly and J.L. Waddington, Neurochem. Int., 2Q(Suppl.). 135s (1992). P.H. Anderson, F.C. Gronvald, R. Hohlweg, L.B. Hansen, E. Guddal and C. Braestrup. Eur. J. Pharmacol., U . 4 5 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14.105 (1992). J.R. Prous, ed.. Annu. Drug Data Rep., 14,765 (1992). H. Bottcher, G. Barnickel, H:H. Hausberg, A.F. Haase, C.A. Seyfried and V. Eiermann, J. Med. Chem., 4020 (1992). K. Wiedemann. A. Loycke, J.C. Krieg and F. Holsboer. Pharmacupsychiafry. 117 (1992). D. Naber, Pharmacopsychiatry,25,88 (1992). J.R. Prous, ed.. Annu. Drug Data Rep., 10 (1992). J.R. Prous, ed., Annu. Drug Data Rep., fi,1 1 (1 992). G. Higgins, lnpharma, 841, 6 (1992) H.Y. Meltzer, Br. J. Psychiatry, ljjQ(Suppl. 17),22 (1992). D. Pickar, R.R. Owen, R.E. Litman, E. Konicki. R. Gutierrez and M.H. Rapaport. Arch. Gen. Psychiatry, 4, 345 (1992). D. L. Buch. Am. Fam. Physician, 795,(1992). J. Hietala, M. Koulu. M. Kuoppamaki and J. Lappalainen, Prog. Neuropsychopharmacol.Biol. Psychiatry, 16,727 (1992). P. Seeman. Neuropsychopharmacol.. 261 (1992). T.I. Lidsky and S.P. Banerjee, Neuroscience Lett.. 100 (1992). U.B. Sunay, K.C. Talbot and V. Galullo. J. Label. Comp. Radiopharm., 1041 (1992). L. Farde and A.L. Nordstrom, Br. J. Psychiatiy, 16p(Suppl. 17). 30 (1992). L. Farde, A.L. Nordstrom, F.A. Wisel, S. Pauli. C. Halldin and G. Sedvall, Arch. Gen. Psychiat.. 4,
53. 54.
R.P. Mason and V. Fischer. Drug Safety, Z (Suppl. l),45 (1992). A.V. Pisciotta, S.A. Konings. L.L. Ciesemier and C.E. Cronkite. Drug Safety, (Suppl. l), 33
31. 32. 33. 34. 35.
36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
66. 67. 68. 69. 70.
a,
a,
u,
e,
z,
m,
a
538 (1992).
z
(1992).
J.P. Uetrecht. Drug Safety, z (Suppl. l), 51 (1992). S.L. Gerson and H. Meltzer. Drug Safety, (Suppl. l), 17 (1992). V. Fischer, B. Vogels, G. Maurer and R.E. Tynes. J. Pharmacol. Exp. Ther., 2§Q 1355 (1992). H. Y. Mekzer and J.F. Nash, Pharmacol. Rev., 587 (1992). A.D. Levy and L.D. Van der Kar, Life Sciences, s,83 (1992). B.L. Roth, R.D. Ciarnello and H.Y. Meltzer, J. Pharmacol. Exp. Ther., 2FLp, 1361 (1992). A. Claus, J. Bollen, H. DeCuyper. M. Eneman, M. Malfroid. J. Peuskens and S.Heylen, Ada Psychiatr. Scand., 85.295 (1992). 0.Blin, J.M. Azorin and P. Bonhours, Clin. Pharmacol. Ther.. 51, 189 (1992). A. Hillert, W. Maier, H.Wetzel and 0. Benkert. Pharmacopsych., 25,105 (1992). L. Koymans, N.P.E. Vermeulen, S.A.B.E. van Acker, J.M. te Koppele, J.J.P. Heykants, K. Lavrijsen, W. Meuldermans and G.M.Donne-Op den Kelder, Chem. Res. Toxicol., 5,211 (1992). J.E. Leysen, P.M.F. Janssen. W. Gommeren, J. Wynants. P.J. Pauwels and P.A.J. Janssen. Mol. Pharmacol.. 494 (1992). A.A.H.P. Megens, F.H.L. Awouters. T.F. Meert, K.H.L. Schellekens, C.J.E. Niemegeers and P.A.J. Janssen. J. Pharmacol. Exp. Ther., 146 (1992). A.A.H.P. Megens, C.J.E. Niemegeers and F.H.L. Awouters, J. Pharmacol. Exp. Ther., 26p, 160
z
a,
a,
m,
(1992).
N.J. Hrib, J.G. Jurcak, F.P. Huger, C.L. Errico and R.W. Dunn, J. Med. Chem., 2, 1068 (1992). L. Davis, R.C. Effland, J.T. Klein, R.W. Dunn. H.M. Geyer and W. W. Petko. Drug Design and Discovery, 8, 225 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14,9 (1992).
48
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.
100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.
McCall, Ed.
Section I-CNSAgents
J. Heym. T. Seeger, P. Seymour, H. Howard, 7. Smolarek, L. Tremaine. K. Wilner, N. Gerber, D. Wong and P. Etienne, Abstr. 31st Ann. Mtg. Amer. Coll. Neuropsychopharmacol., Dec 14-18. 1992, San Juan, PR. J.R. Prous, ed., Annu. Drug Data Rep., 14, 567 (1992). H.H. Friberg, T. Skarsfeldt, M. Pierce. M. Mason, T. Sebree and J. McKelvy, Schiz. Res.. 6,111 (1992). C.R. Rasmussen, US Patent 5,075,315 (1992). 23 (1992). Scrip, PharmaProjects, 2, a1320 (1992). Scrip, 15 (1992). Scrip, 23 (1992). S.M. Sorensen, C.J., Schmidt, T.M. Humphreys and J.H. Kehne. Abstr. 22nd Ann. Mtg. SOC.for Neurosciences, Ocf. 25-30,1992. Anaheim. CA. D. Damour, R. Labaudiniere, J.-L. Malleron and S. Mignani, EP Appl. 51 1,074 (1992). J.W. Newcomer, W.O. Faustman. R.B. Zipursky and J.G. Csernansky. Arch. Gen. Psychiatry, 49, 751 (1992). S. Jegham, G. Defosse. T. Purcell and J. Schoemaker, EP Appl. 507,650 (1992). T.P. Blackburn, G. Kennett, C.R. Ashby. Y. Minabe. R.Y. Wang. A.M. Dorneney and B. Costell, Abstr. 2nd Int. Symp. Serotonin. Sept. 15-18, 1992, Houslon. TX. p5. M.S. Chambers, R. Baker, D.C. Billington, A.K. Knight, D.L. Middlemass and E.H.F. Wong, J. Med. Chem.. 2033 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14, 10 (1992). L. Cook, S.W. Tam and K.W. Rohrbach, J. Pharmacol. Exp. Ther., 1159 (1992). S.W. Tam, G.F. Steinfels, P.J. Gilligan, W.K. Schmidt and L.J. Cook, J. Pharmacol. Exp. Ther.. 2& 1167 (1992). S.G. Culp, D. Rominger, S.W. Tam and E.B. De Souza, J. Pharmacol. Exp. Ther.. iS3, 1175 (1992). AS. Wright, E. Ciganek. D.E. Grigoriadis, J. McElroy, K.W. Rohrbach, W.K. Schmidt and S.W. Tam, Abstr, Amer. Chem. SOC.203rd Ann. Natl. Mtg., Apr. 5-10, 1992, San Francisco, CA, MEDl 77. W.D. Bowen, J.M. Walker, B.R. DeCosta, R. Wu. P.J. Tolentino, D. Finn, R.B. Rothman and K.C. Rice, J. Pharmacol. Exp. T h e r . , B , 32 (1992). B.R. DeCosta, L. Radesca, L. DiPaolo and W.D. Bowen, J. Med. Chem., 3,38 (1992). R.H. Erickson, K.J. Natalie. W. Bock, 2. Lu, F. Farzin, R.G. Sherrill, D.G. Meloni, R.J. Palch, W.J. Rzesotarski, J. Clifton, M.J. Pontecorvo, M.A. Bailey, K. Naper and W. Karbon, J. Med. Chem.. 3 , 1526 (1992). P.Malekahmadi, Neurosci. Biobehav. Rev., 16,365 (1992). F. Boix, R. Mattioli, F. Adams. J.P. Huston and R.K. Schwarti, Eur. J. Pharmacol., 103 (1992). S.A. Chepurno, N.E. Chepurno. E. Paschali. N.Y. Pantalee and I.P. Ashmarin, Reg. Pept., 45 (Suppl. l ) , 545 (1992). J.A. Lowe, S.E. Drozda, E.M. Snider, K.P. Longo. S.H. Zorn, J. Morrone. E.R. Jackson, S. McLean, D. K. Bryce, J. Bordner. A. Nagahisa. Y. Kanai. 0. Suga and M. Tsuchiya, J. Mad. Chem., 3 , 2 5 9 1 (1992). J.A.Lowe. DrugsFuture,JJ. 1115 (1992). R. Baker, C. Swain and E.M. Seward, EP Appl. 499.313 (1992). A. Carruette. F. Montier, S. Moussaoui, B. Charles, V. Fardin and A. Champion, Fund. Clin. Pharmacol., 2, 813 (1992). L. Pradier, M. Laville. S. le Guern, J.P. Hubert and A. Doble, Br. J. Pharmacol., X& 79P (1992). V. Fardin, F. Foucault, M.D. Bock and C. Garrett, Br. J. Pharmacol., 1p5.BOP (1992). M. Tabart, Abstr. XI1 In!. Symp. Med. Chem., Sept 13-17, 1992, Basel, SW. B.R. Venepalli. L.D. Aimone, K.C. Appell, M.R. Bell, J.A. Dority, R. Goswami, P.L. Hall, V. Kumar, K.B. Lawrence, M.E. Logan, P.M. Scensny, J.A. Seelye, B.E. Tomczuk and J.M. Yanni, J. Med. Chem., 3 , 3 7 4 (1992). K.B. Lawrence, B.R. Venepaili. K.C. Appell. R. Goswami, M.E.Logan. B.E. Tomczuk and J.M. Yanni, J. Med. Chem., 1273 (1992). N.P. Gerard and C. Gerard, WO Patent Appl. 9216547 (1992). K. Rasmussen, M.E. Stockton, J.F. Czachura and J.J. Howbert. Eur. J. Pharmacol., 2p9, 135 (1992). R. Kerwin. P. Robinson and J. Stephenson, Psychol. Med., 22, 37 (1992). K. Fuxe, L.F. Agnati, G. VonEuler, S.Tanganelli, W.T. OConnor. S.Ferre, P. Hedlund and M. Zoli, Neurochem. Int., (Suppl.). 215s (1992). D.J. Rossi, M.F. Jarvis and G.E. Martin. FASEB, 6 I008 (1992), J.T. Greenamyre, Arch. Neurol., &,901 (1992). 8.0. Kretschmer and W.J. Schmidt, Clin. Neuropharmacol., 15,157 (1992). A. Delini-Stula,D. Berdah-Tordjman and N. Neumann. Clin. Neuropharmacol., j5 (Suppl.), 405A (1992). M. J. Owen and M. McGill, Clin. Neuropharmacol., (Suppl.), 222A (1992).
m, m, m,
a,
a,
m,
a,
a
Chap. 5
114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141.
Antipsychotics
Howard, Seeger 4*L
m,
M. Owen and P. McGuffin, Br. Med. Journal, 664 (1 992). H.W. Moises. C. Wiese and L. Yang. Nervenheilk. 11,248 (1992). J. Hallmayer. W. Maier, M. Ackenheil. M.A. E d , S. Schmidt, J. Minges, D. Lichtermann and D. Wildenauer. Biol. Psychiatry, 3,83 (1992). P.C. Sham, E. OCallaghan. N. Takei, G.K. Murray, E.H. Hare and R.M. Murray, Br. J. Psychiatry,
m 4 6 1 (1992). J.M. Eagles, Br. J. Psychiatry, 160,598 (1992). M. Fux. I. Sarov, Y. Ginot and B. Sarov, Isr. J. Psychiatry, 29,33 (1992). S.J. Cooper, Br. J. Psychiatry, 16t394 (1992). J. Knight, A. Knight and G. Ungvari. Br. J. Psychiatry, 16p, 533 (1992). H.A. Teplizki, B. Sela and Y. Schoenfeld, Immun. Res., 66 (1992).
u,
A. Galinowski. R. Barbouche. P. Truffinet, H. Louzir, M.F. Poirier, 0. Bouret. H. Loo and S. Avrameas, Acta Psychiatr. Scand., 85,240 (1992). R.S. Smith, Med. Hypoth.. 27 (1992). H. Kaiya. Prost. Leuko. Essent. Fatty Acids, G, 33 (1992). P. Riederer, K.W. Lange. J. Kornhuber and W. Danielczyk, Arzn. Forsch.. 265 (1992). C.G. Swahn, L. Farde. C. Halldin and G. Sedvall. Hum. Psychopharmacol., 97 (1992). C.A. Tamminga, G.K. Thaker, R. Buchanan, B. Kirkpatrick. L.D. Alphs, T.N. Chase and W.T. Carpenter, Arch. Gen. Psychiatry, 49 522 (1992). S.W. Lewis, R.A. Ford, G.M. Syed, A.M. Reveley and B.K. Toone, Psychol. Med.. 22 ,27(1 992). L.S. Pilowsky, D.C. Costa, P.J. Ell. R.M. Murray, N.P. Verhoeff and R.W. Kerwin, Lancet, 199
x,
a, z,
(1 992). F.A. Wiesel, Clin. Neuropharmacol., l.5 (Suppl. l ) , 460A (1992)..
m,
L. Farde. A.L. Nordstrom, C. Halldin. F.A. Wiesel and G. Sedvall, Clin Neuropharmacol.,15 (Suppl. 1). 46BA (1992). D.F. Wong. Neuropsych.,Z. 69 (1992). P. Bukley, E. OCallaghan, C. Larkin. 0. Redmond, J. Stack and J.L. Waddington. Biol. Psychiatry,
a,209 (1992).
M.E. Shenton, R. Kikinis, F.A. Tolesz, S.D. Pollak, M.LeLay, C.G. Wible, H. Hokama. J. Martin, D Metcalf and M. Coleman, N. Eng. J. Med., 604 (1992). W. Gunther. Prog. Neuropsychopharmacol. Biol. Psychiatry, Ifl,445 (1992). R.E.Gur, J. Neur.Trans.-G.. 13 (1992). M. Memo, C. Missale. M. Pizzi and P.F. Spano, Clin. Neuropharmacol.,15(Suppl. I), 458A (1992). S.G.Dahl, 0. Edvardsen and I. Sylte, Therapie, 4.6, 453 (1991). I. Penersson and T. Liljefors, J. Med. Chem., 2355 (1992). Y. Machiyama, Schizophr. Bull., B,107 (1992).
m,
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introduction - The discovery of novel atypical antipsychotic agents with efficacy against both
positive and negative symptoms, along with a reduced side effects profile, remains a primary goal in the treatment of schizophrenia (1-3). During the past year a number of reviews have appeared which cover emerging therapies (4-6) as well as the clinical performance of more advanced candidates including remoxipride (7-9) and risperidone (10-13). Additional studies have examined agents such as bromocryptine (14), fluvoxamine (15). mianserin (16), levopromazine (17) and zotepine (18), alone or as adjunctive therapies, for control of negative symptoms or for the treatment-resistant patient.
- Further characterization of newly identified dopamine receptors (D3, D4, D5) has included the first autoradiographic visualization of D3 receptors in rat (19) and human brain (20). The D4 receptor has been found to exist as several polymorphic variants, which may explain the genetic range of susceptibility to schizophrenia and / or varied individual response to antipsychotics (21). Agents with highly selective antagonist activity for any of the newly discovered dopamine receptors have not yet been described, although antagonism of D4 receptors is of interest as a new target (22). There has also been considerable activity in the cloning and expression of dopamine receptors during the year, including work with the D l b (23), D2 (24, 25), D3 (26) and human D4 subtypes (27). Levels of mRNA for D1, 02, D3 and 05 receptors in rat brain after neuroleptic treatment have been measured (28.29). e (DAl Rec- In addition to remoxipride ( l ) ,a variety of Dq-receptor selective antagonists are reportedly under review. For example, RWJ-25730 (2)emerged as one of the most potent analogs from a series of disubslituted pyrroles (30). Two structurally similar pyrimidinylpiperazines 3 and 4 have been disclosed which show potent D2 and 5-HTla antagonism and inhibition of locomotor activity in mice (31). A benzyl substituted analog of spiperone with high 02 affinity has been proposed as a potential PET tracer for !A&? D2 receptor occupancy studies (32).
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Section I-CNS Agents
McCall, Ed
Antagonism of doparnine D1 receptors has also been proposed as a method for the control of negative symptomatology in schizophrenia (33, 34). Among the more recently discovered D1selective antagonists are NNC-687 (6) and some compounds from a series of tricyclic derivatives, e.g., 1, which have proven active in the inhibition of conditioned avoidance response in squirrel monkeys (35,36). A series of benzophenanthridines (e.g., 8) inhibit dopamine stimulation of adenylate cyclase activity and may possess cognition enhancement properties (37).
- Clinical trials with roxindole (EMD-49,980, $), a Dp autoreceptor agonist, showed efficacy in a group of schizophrenic patients with primary negative symptoms (38, 39), whereas, results with SDZ-HDZ912 (Ip)have been less conclusive (40). Two autoreceptor agonists with selectivity for D2 receptors - PD-135222 (1L)and PD-138276 (12)- reduce amphetamine and apomorphine-inducedlocomotor activity in mice (41, 42).
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The virtues of this atypical antipsychotic continue to be extolled (43-46). Debate on the novel mechanisrn(s) of action of clozapine continues: its superior efficacy has been attributed to interactions with a variety of receptor sites in the CNS, and this list has been expanded to include 5HTlc (47), D4 (48) and glutamate (49). The syntheses of 3H- and 14C-labelledu f o r mechanistic and metabolism studies have been described (50). A PET study using showed that, within the efficaciousdose range, a 36-52% D1 receptor occupancy could be achieved versus a 38-63% level for D2 sites (51), as compared to 70-90% occupancy seen with standard agents (52). The possible mechanisms underlying the development of agranulocytosis associated with have been investigated. One proposal emphasizes a free-radical formation which may produce proteinadducts and subsequent induction of antibodies to these conjugates: the use of appropriate levels of ascorbate has been recommended for inhibition of free radical-mediatedreactions. (53). Other similar immune response mechanisms have been proposed (54-57).
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in 15-HTI Ant- The relevence of interactions of antipsychotic agents with serotoninergic receptors has been recently reviewed (58-60). In a 12-week double-blind study with treatment refractory subjects, patients receiving risperidone (14)required ten times less anti-
Chap. 5
Howard, Seeger 41.
Antipsychotics
Parkinsonism medication than those on haloperidol (61); efficacy has also been demonstrated in patients with coexisting anxiety or depressive syndromes (62, 63). hyitrP and hyiUn, 14 is oxidized by cytochrome P4502D6 at the 9- and 7-positions of the tetrahydropyridopyrirnidinone portion of the molecule (64). Ocaperidone (R 79,598, also combines potent 5-HT2 and Dp antagonism (65, 66); preclinical data suggest that should produce less extrapyramidal side effects (EPS) (67). other benzisoxazoles which display a similar preclinical profile are the piperidine HP-873 (B) which has entered Phase 1 I clinical evaluation (68), the piperazine HRP-392 which which inhibited inhibited apomorphine-induced climbing in mice (69) and piperidine methylphenidate-induced stereotypy without producing catalepsy (70).
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The benzisothiazolylpiperazinemoiety is also a common pharmacophore in several new combined D2 / 5-HT2 antagonists. For example, CP-88,059 (19), like SM-9018 shows high affinity and selectivity for 5-HT2 vs D2 receptors in rat; at an oral dose of 40 mg 19,PET studies determined a 70% Dp occupancy in the putamen vs the 02-selective antagonist [llC]-raclopride (71). A series of analogs including also bind with high affinity to the D2 receptor and show little potential for side effects based upon the low level of catalepsy induction (72). The Dp / 5-HT2 selective antagonist, settindole (2) has been evaluated in normal subjects for safety and tolerance (73). Finally, a series of indeno[l,2-c]pyridines, from which was exemplilied, combines selective Dp and 5-HT2 antagonism to give compounds which are active in the apomorphine-inducedclimbing assay (74).
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Section I-CNSAgents
McCall. Ed.
a,
Structurally similar to olanzepine (LY-170053,a) combines D2 and 5-HT2 antagonism with high affinity for the D1 receptor; it was tolerated in man with no evidence of agranulocytosis (75). The dibenzothiazepin lCl-204,636 displaying affinity for both D2 and 5-HT2 receptors, has demonstrated efficacy in man with insomnia, sedation and transient sinus tachycardia being the major side effects reported (76, 77). Org-5222 (25)and Org-10490 (2L) each exhibit potent antagonism of Dp and 5-HT2 receptors and are relatively free of EPS by comparison with other agents in recent clinical trials (73, 78).
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24 Some investigators have continued to evaluate serotonin antagonists which possess little or no affinity for dopamine receptors as possible neuroleptics with minimal side effects potential. MDL100,907 is among the most 5-HT2-selective antagonists, with weak affinity for D2, 5-HTla and at sites and with behavioral and etectrophysiological activities consistent with that of an atypical antipsychotic agent (79). Also claimed to be selective 5-HT2 antagonists are a number of benzimidazolones such as 29 (80).
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In a single-blind trial of neuroleptic efficacy with eight symptomatic patients, the 5-HTg-selective antagonist zacopride produced no significant improvements; almost all subjects experienced mild to moderate sedation and no significant changes in mean HVA or plasma prolactin levels were detected (81). Benzirnidazolylpiperidines, such as are claimed to be 5-HT3 and/or 5-HT4 antagonists with potential antipsychotic activity (82). BRL-46470A has been mentioned as a possible antipsychotic agent with reduced EPS potential (83).
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- The potential role of sigma (0)receptors in the etiology of psychosis has been discussed previously (see Chapter 1, this volume). Spiropiperidine analogs such as p have been claimed as among the most o-selective compounds yet reported (84). The oxime PD-128,298 (& is a I), selective Q antagonist which showed no EPS in haloperidol-sensitizedmonkeys (as),while DuP734 is selective for both CJ and 5-HT2 receptors, blocked mescaline-induced scratching and aggressive activity, and only weakly reversed APO-induced climbing, suggesting a low EPS potential (86-88). The novel CJ antagonist XJ-887 in addition to being a potent CJ and 5-HT2
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Howard. Seeger
Antipsychotics
Chap. 5
a
antagonist, displayed exceptional activity in the mescaline scratch assay and isolation-induced aggression model (89). Evaluation of a series of compounds related to the cyclohexane-diamine 80-737 90) demonstrated that enhanced potency and selectivity could be achieved through (91). From a series of arninoalkoxythe greater conformational flexibility of acyclic diamines like chromones. NPC-16377 was found to reverse amphetamine-induced locomotion in mice (92).
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- Inhibition of neurokinin NK1 receptors in the CNS has been been postulated as a means of regulating dopaminergic activity indirectly, thus minimizing the potential side effects associated with overt dopamine receptor blockade (93-95). The recent availahility of selective, nonpeptide antagonists such as CP-96,345 has heightened interest in this approach; the SAR surrounding 4p has been published (96, 97) and a related ether series has also been disclosed (98). Other prototypical antagonists include the NK1selective amidine RP-67580 (41, 99-102) and a series of androstano[3,2-b]pyrimido(l,2-a]benzimidazolesfrom which WIN-51708 (42)was one of the most potent h w (103). Naphthimidazolium derivatives (e.g., 4.3)have demonstrated efficacy in a rat salivation assay (104). The human NK1 receptor gene has been cloned and expressed from a human IM-9lymphocyte cell library. (105).
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Sectlon I-CNS Agents
44
McCall. Ed.
-
Several additional receptors have been proposed as having a potential role in the alleviation of psychotic symptoms. Cholecystokinin (CCK) receptors, upon exposure to the CCK-B selective antagonist LY-262691 produced a reduction in the number of spontaneously active A9 and A10 dopamine neurons in the rat (106). An autoradiographic study has determined an alteration in the distribution of CCK receptors in schizophrenic brain (107). Regulation of Dp receptors yia adenosine Apelective agonists has been postulated as an alternative means of control (108, 109). Partial or full agonists for the glycine "co-agonist" site on the NMDA receptor may be useful in the treatment of schizophrenia without producing excitotoxicity (110) . Glycine agonists may, however, exacerbate symptoms for some patients, and their utility needs to be more fully investigated (111). Partial benzodiazepine agonists have also been proposed as yet another means of controlling psychotic behavior (112).
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- The genetic factor in the development of schizophrenia has been further emphasized (113-116). as has the incidence of the disease due to prior exposure to viral pathogens. (117-120). The role of autoantibodies in the onset of psychosis has similarly been examined (121-124) and hypotheses related to imbalances in second messenger systems (125) and glutamate levels (126) have been advanced. . .
- A variety of studies have been directed at understanding the interaction of neuroleptics with CNS receptors utilizing PET (127-133) and MRI techniques (134-137). Molecular modelling studies, focused upon interactions between, for example, 5-HT1a, 5-HT2 and D2 receptors and their corresponding ligands, have estimated the conformational changes which may be necessary for optimal antagonism (138-140).
- A model of schizophrenia using a chronic methamphetamine intoxication protocol has been demonstrated (141). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17. 18. 19. 20. 21. 22. 23.
A. Carlsson, Clin.Neuropharmacol,, &(Suppl. l), 271A (1992). J.M. Kane, BulLMenninger Clin., f&, 62 (1992). S. Hughes, Scrip Mag., 2, 50 (1992).
M.D. Tricklebank. L.J. Bristow and P.H. Hutson, Prog. Drug Res.. 3, 299 (1992). G.P. Reynolds, Trends Pharmacol. Sci., 116, (1992). N.J. Hrib, Chem. Ind.,& 213 (1992). T. Lewander, Clin. Neuropharmacol., l5(Suppl. l), 269A (1992). D.J. King, M. Blomqvist, S.J. Cooper, M.M. Doherty. M.J. Mitchell and R.C. Montgomery, Psychopharmacology, 1pz. 175 (1992). M. Mitchell and 8. Tandberg, Drugs of Today, 28.249 (1992). R.L. Borison, A.P. Pathiraja, 6.1. Diamond and R.C. Meibach, Psychopharmacol. Bull., 28.213
u,
(1992).
A. Claus, J. Bollen, H. Decuyper, M. Eneman, M. Malfroid, J. Peuskens and S. Heylen. Acta Psychiatr. Scand., 85, 295 (1992). F. Muller-Spahn, Clin. Neuropharmacol., fi(Suppl. l ) , 90A (1992). S.L. Heylen and Y.G. Gelders, Clin. Neuropharmacol., 15 (Suppl. l), 18OA (1992). M.A. Wolf, J.M. Diener, C. Lajeunesse and C. Shriqui, Biol. Psychiat., 1166 (1992). H. Silver and A. Nassar, Biol. Psychiat.. 698 (1992). Y. Mizuki. N. Kajimura. S. Kai, M. Suetsugi and I. Ushijima, Prog. Neuropsychopharmacol.Biol. Psychiat., 16,517 (1992). S. La1 and N.P. Nair, Acta Psychiatr. Scand., &,243 (1992). C. Barnas, C.H. Stuppaeck, C. Miller, C. Haring. Sprner, B. Unterweger and W.W. Fleischhacker, Int. J. Clin. Psychopharmacol., Z,23 (1992). D. Levesque, J. Diaz, C. Pilon, M-P. Martres. B. Giros, E. Souil. D. Schott, J.-L. Morgat, J.C. Schwartz and P. Sokoloff, Proc. Natl. Acad. Sci. USA., 89, 8155 (1992). A.M. Murray, H. Ryoo and J.N. Joyce, Eur. J. Pharmacol., 222.443(1992). H.H.M. Van Tol, C.M. Wu, H . 4 . Guan, K. Ohara, J.R. Bunzow, 0. Civelli. J. Kennedy, P. Seeman. H.B. Niznik and V. Jovanovic, Nature, 35Q,149 (1992). G. Higgins. InPharma. 842. 8 (1992). M. Tlberi, K.R. Jarvie and M.G. Caron, WO 9218533 (1992).
a,
z,
Chap. 5
24. 25. 26. 27. 28. 29. 30.
Howard, Beeger 48
Antipsychotics
w,
G. Higgins, InPharma. 8 (1992). P. Seeman, H.C. Guan. 0. Civelli, H.H.M. Van Tol. R.K. Sunahara and H.B. Niznik, Eur. J. Pharmacol. Mol. Pharm.. 222. 139 (1992). 8. Giros, P. Sokoloff,J.C. Schwartz and M.P. Martres, WO 9207937 (1992). 0. Civelli and H. Van Tol. WO 9210571 (1 9921. P.R. Buckland, M.C. Odonovan and P.' McGuff in, Psychopharmacol., 479 (1992). J.H. Meadorwoodruff. A. Mansour, D.K. Grandy. S.P. Damask, 0. Civelli and S.J. Watson, Neurosci. Lett., &&. 209 (1992). M.K. Scott, M.E. Martin, D.L. DeStefano. C.L. Fedde, M.J. Kukla and D.L. Barrett. J. Med. Chem.,
m,
g,552 (1992).
48. 49. 50 51. 52.
J.R. Prous, ed., Annu. Drug Data Rep., 14.103 (1992). R.H. Mach, J.R. Jackson, R.R. Luedtke. K.J. Ivins. P.B. Molinoff and R. L. Ehrenkaufer, J. Med. Chem.,& 423 (1992). M.R. Lynch, Prog. Neuropsychopharmacol. Biol. Psychiat., 16,797 (1992). S.A. Daly and J.L. Waddington, Neurochem. Int., 2Q(Suppl.). 135s (1992). P.H. Anderson, F.C. Gronvald, R. Hohlweg, L.B. Hansen, E. Guddal and C. Braestrup. Eur. J. Pharmacol., U . 4 5 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14.105 (1992). J.R. Prous, ed.. Annu. Drug Data Rep., 14,765 (1992). H. Bottcher, G. Barnickel, H:H. Hausberg, A.F. Haase, C.A. Seyfried and V. Eiermann, J. Med. Chem., 4020 (1992). K. Wiedemann. A. Loycke, J.C. Krieg and F. Holsboer. Pharmacupsychiafry. 117 (1992). D. Naber, Pharmacopsychiatry,25,88 (1992). J.R. Prous, ed.. Annu. Drug Data Rep., 10 (1992). J.R. Prous, ed., Annu. Drug Data Rep., fi,1 1 (1 992). G. Higgins, lnpharma, 841, 6 (1992) H.Y. Meltzer, Br. J. Psychiatry, ljjQ(Suppl. 17),22 (1992). D. Pickar, R.R. Owen, R.E. Litman, E. Konicki. R. Gutierrez and M.H. Rapaport. Arch. Gen. Psychiatry, 4, 345 (1992). D. L. Buch. Am. Fam. Physician, 795,(1992). J. Hietala, M. Koulu. M. Kuoppamaki and J. Lappalainen, Prog. Neuropsychopharmacol.Biol. Psychiatry, 16,727 (1992). P. Seeman. Neuropsychopharmacol.. 261 (1992). T.I. Lidsky and S.P. Banerjee, Neuroscience Lett.. 100 (1992). U.B. Sunay, K.C. Talbot and V. Galullo. J. Label. Comp. Radiopharm., 1041 (1992). L. Farde and A.L. Nordstrom, Br. J. Psychiatiy, 16p(Suppl. 17). 30 (1992). L. Farde, A.L. Nordstrom, F.A. Wisel, S. Pauli. C. Halldin and G. Sedvall, Arch. Gen. Psychiat.. 4,
53. 54.
R.P. Mason and V. Fischer. Drug Safety, Z (Suppl. l),45 (1992). A.V. Pisciotta, S.A. Konings. L.L. Ciesemier and C.E. Cronkite. Drug Safety, (Suppl. l), 33
31. 32. 33. 34. 35.
36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
66. 67. 68. 69. 70.
a,
a,
u,
e,
z,
m,
a
538 (1992).
z
(1992).
J.P. Uetrecht. Drug Safety, z (Suppl. l), 51 (1992). S.L. Gerson and H. Meltzer. Drug Safety, (Suppl. l), 17 (1992). V. Fischer, B. Vogels, G. Maurer and R.E. Tynes. J. Pharmacol. Exp. Ther., 2§Q 1355 (1992). H. Y. Mekzer and J.F. Nash, Pharmacol. Rev., 587 (1992). A.D. Levy and L.D. Van der Kar, Life Sciences, s,83 (1992). B.L. Roth, R.D. Ciarnello and H.Y. Meltzer, J. Pharmacol. Exp. Ther., 2FLp, 1361 (1992). A. Claus, J. Bollen, H. DeCuyper. M. Eneman, M. Malfroid. J. Peuskens and S.Heylen, Ada Psychiatr. Scand., 85.295 (1992). 0.Blin, J.M. Azorin and P. Bonhours, Clin. Pharmacol. Ther.. 51, 189 (1992). A. Hillert, W. Maier, H.Wetzel and 0. Benkert. Pharmacopsych., 25,105 (1992). L. Koymans, N.P.E. Vermeulen, S.A.B.E. van Acker, J.M. te Koppele, J.J.P. Heykants, K. Lavrijsen, W. Meuldermans and G.M.Donne-Op den Kelder, Chem. Res. Toxicol., 5,211 (1992). J.E. Leysen, P.M.F. Janssen. W. Gommeren, J. Wynants. P.J. Pauwels and P.A.J. Janssen. Mol. Pharmacol.. 494 (1992). A.A.H.P. Megens, F.H.L. Awouters. T.F. Meert, K.H.L. Schellekens, C.J.E. Niemegeers and P.A.J. Janssen. J. Pharmacol. Exp. Ther., 146 (1992). A.A.H.P. Megens, C.J.E. Niemegeers and F.H.L. Awouters, J. Pharmacol. Exp. Ther., 26p, 160
z
a,
a,
m,
(1992).
N.J. Hrib, J.G. Jurcak, F.P. Huger, C.L. Errico and R.W. Dunn, J. Med. Chem., 2, 1068 (1992). L. Davis, R.C. Effland, J.T. Klein, R.W. Dunn. H.M. Geyer and W. W. Petko. Drug Design and Discovery, 8, 225 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14,9 (1992).
48
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.
100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.
McCall, Ed.
Section I-CNSAgents
J. Heym. T. Seeger, P. Seymour, H. Howard, 7. Smolarek, L. Tremaine. K. Wilner, N. Gerber, D. Wong and P. Etienne, Abstr. 31st Ann. Mtg. Amer. Coll. Neuropsychopharmacol., Dec 14-18. 1992, San Juan, PR. J.R. Prous, ed., Annu. Drug Data Rep., 14, 567 (1992). H.H. Friberg, T. Skarsfeldt, M. Pierce. M. Mason, T. Sebree and J. McKelvy, Schiz. Res.. 6,111 (1992). C.R. Rasmussen, US Patent 5,075,315 (1992). 23 (1992). Scrip, PharmaProjects, 2, a1320 (1992). Scrip, 15 (1992). Scrip, 23 (1992). S.M. Sorensen, C.J., Schmidt, T.M. Humphreys and J.H. Kehne. Abstr. 22nd Ann. Mtg. SOC.for Neurosciences, Ocf. 25-30,1992. Anaheim. CA. D. Damour, R. Labaudiniere, J.-L. Malleron and S. Mignani, EP Appl. 51 1,074 (1992). J.W. Newcomer, W.O. Faustman. R.B. Zipursky and J.G. Csernansky. Arch. Gen. Psychiatry, 49, 751 (1992). S. Jegham, G. Defosse. T. Purcell and J. Schoemaker, EP Appl. 507,650 (1992). T.P. Blackburn, G. Kennett, C.R. Ashby. Y. Minabe. R.Y. Wang. A.M. Dorneney and B. Costell, Abstr. 2nd Int. Symp. Serotonin. Sept. 15-18, 1992, Houslon. TX. p5. M.S. Chambers, R. Baker, D.C. Billington, A.K. Knight, D.L. Middlemass and E.H.F. Wong, J. Med. Chem.. 2033 (1992). J.R. Prous, ed., Annu. Drug Data Rep., 14, 10 (1992). L. Cook, S.W. Tam and K.W. Rohrbach, J. Pharmacol. Exp. Ther., 1159 (1992). S.W. Tam, G.F. Steinfels, P.J. Gilligan, W.K. Schmidt and L.J. Cook, J. Pharmacol. Exp. Ther.. 2& 1167 (1992). S.G. Culp, D. Rominger, S.W. Tam and E.B. De Souza, J. Pharmacol. Exp. Ther.. iS3, 1175 (1992). AS. Wright, E. Ciganek. D.E. Grigoriadis, J. McElroy, K.W. Rohrbach, W.K. Schmidt and S.W. Tam, Abstr, Amer. Chem. SOC.203rd Ann. Natl. Mtg., Apr. 5-10, 1992, San Francisco, CA, MEDl 77. W.D. Bowen, J.M. Walker, B.R. DeCosta, R. Wu. P.J. Tolentino, D. Finn, R.B. Rothman and K.C. Rice, J. Pharmacol. Exp. T h e r . , B , 32 (1992). B.R. DeCosta, L. Radesca, L. DiPaolo and W.D. Bowen, J. Med. Chem., 3,38 (1992). R.H. Erickson, K.J. Natalie. W. Bock, 2. Lu, F. Farzin, R.G. Sherrill, D.G. Meloni, R.J. Palch, W.J. Rzesotarski, J. Clifton, M.J. Pontecorvo, M.A. Bailey, K. Naper and W. Karbon, J. Med. Chem.. 3 , 1526 (1992). P.Malekahmadi, Neurosci. Biobehav. Rev., 16,365 (1992). F. Boix, R. Mattioli, F. Adams. J.P. Huston and R.K. Schwarti, Eur. J. Pharmacol., 103 (1992). S.A. Chepurno, N.E. Chepurno. E. Paschali. N.Y. Pantalee and I.P. Ashmarin, Reg. Pept., 45 (Suppl. l ) , 545 (1992). J.A. Lowe, S.E. Drozda, E.M. Snider, K.P. Longo. S.H. Zorn, J. Morrone. E.R. Jackson, S. McLean, D. K. Bryce, J. Bordner. A. Nagahisa. Y. Kanai. 0. Suga and M. Tsuchiya, J. Mad. Chem., 3 , 2 5 9 1 (1992). J.A.Lowe. DrugsFuture,JJ. 1115 (1992). R. Baker, C. Swain and E.M. Seward, EP Appl. 499.313 (1992). A. Carruette. F. Montier, S. Moussaoui, B. Charles, V. Fardin and A. Champion, Fund. Clin. Pharmacol., 2, 813 (1992). L. Pradier, M. Laville. S. le Guern, J.P. Hubert and A. Doble, Br. J. Pharmacol., X& 79P (1992). V. Fardin, F. Foucault, M.D. Bock and C. Garrett, Br. J. Pharmacol., 1p5.BOP (1992). M. Tabart, Abstr. XI1 In!. Symp. Med. Chem., Sept 13-17, 1992, Basel, SW. B.R. Venepalli. L.D. Aimone, K.C. Appell, M.R. Bell, J.A. Dority, R. Goswami, P.L. Hall, V. Kumar, K.B. Lawrence, M.E. Logan, P.M. Scensny, J.A. Seelye, B.E. Tomczuk and J.M. Yanni, J. Med. Chem., 3 , 3 7 4 (1992). K.B. Lawrence, B.R. Venepaili. K.C. Appell. R. Goswami, M.E.Logan. B.E. Tomczuk and J.M. Yanni, J. Med. Chem., 1273 (1992). N.P. Gerard and C. Gerard, WO Patent Appl. 9216547 (1992). K. Rasmussen, M.E. Stockton, J.F. Czachura and J.J. Howbert. Eur. J. Pharmacol., 2p9, 135 (1992). R. Kerwin. P. Robinson and J. Stephenson, Psychol. Med., 22, 37 (1992). K. Fuxe, L.F. Agnati, G. VonEuler, S.Tanganelli, W.T. OConnor. S.Ferre, P. Hedlund and M. Zoli, Neurochem. Int., (Suppl.). 215s (1992). D.J. Rossi, M.F. Jarvis and G.E. Martin. FASEB, 6 I008 (1992), J.T. Greenamyre, Arch. Neurol., &,901 (1992). 8.0. Kretschmer and W.J. Schmidt, Clin. Neuropharmacol., 15,157 (1992). A. Delini-Stula,D. Berdah-Tordjman and N. Neumann. Clin. Neuropharmacol., j5 (Suppl.), 405A (1992). M. J. Owen and M. McGill, Clin. Neuropharmacol., (Suppl.), 222A (1992).
m, m, m,
a,
a,
m,
a,
a
Chap. 5
114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141.
Antipsychotics
Howard, Seeger 4*L
m,
M. Owen and P. McGuffin, Br. Med. Journal, 664 (1 992). H.W. Moises. C. Wiese and L. Yang. Nervenheilk. 11,248 (1992). J. Hallmayer. W. Maier, M. Ackenheil. M.A. E d , S. Schmidt, J. Minges, D. Lichtermann and D. Wildenauer. Biol. Psychiatry, 3,83 (1992). P.C. Sham, E. OCallaghan. N. Takei, G.K. Murray, E.H. Hare and R.M. Murray, Br. J. Psychiatry,
m 4 6 1 (1992). J.M. Eagles, Br. J. Psychiatry, 160,598 (1992). M. Fux. I. Sarov, Y. Ginot and B. Sarov, Isr. J. Psychiatry, 29,33 (1992). S.J. Cooper, Br. J. Psychiatry, 16t394 (1992). J. Knight, A. Knight and G. Ungvari. Br. J. Psychiatry, 16p, 533 (1992). H.A. Teplizki, B. Sela and Y. Schoenfeld, Immun. Res., 66 (1992).
u,
A. Galinowski. R. Barbouche. P. Truffinet, H. Louzir, M.F. Poirier, 0. Bouret. H. Loo and S. Avrameas, Acta Psychiatr. Scand., 85,240 (1992). R.S. Smith, Med. Hypoth.. 27 (1992). H. Kaiya. Prost. Leuko. Essent. Fatty Acids, G, 33 (1992). P. Riederer, K.W. Lange. J. Kornhuber and W. Danielczyk, Arzn. Forsch.. 265 (1992). C.G. Swahn, L. Farde. C. Halldin and G. Sedvall. Hum. Psychopharmacol., 97 (1992). C.A. Tamminga, G.K. Thaker, R. Buchanan, B. Kirkpatrick. L.D. Alphs, T.N. Chase and W.T. Carpenter, Arch. Gen. Psychiatry, 49 522 (1992). S.W. Lewis, R.A. Ford, G.M. Syed, A.M. Reveley and B.K. Toone, Psychol. Med.. 22 ,27(1 992). L.S. Pilowsky, D.C. Costa, P.J. Ell. R.M. Murray, N.P. Verhoeff and R.W. Kerwin, Lancet, 199
x,
a, z,
(1 992). F.A. Wiesel, Clin. Neuropharmacol., l.5 (Suppl. l ) , 460A (1992)..
m,
L. Farde. A.L. Nordstrom, C. Halldin. F.A. Wiesel and G. Sedvall, Clin Neuropharmacol.,15 (Suppl. 1). 46BA (1992). D.F. Wong. Neuropsych.,Z. 69 (1992). P. Bukley, E. OCallaghan, C. Larkin. 0. Redmond, J. Stack and J.L. Waddington. Biol. Psychiatry,
a,209 (1992).
M.E. Shenton, R. Kikinis, F.A. Tolesz, S.D. Pollak, M.LeLay, C.G. Wible, H. Hokama. J. Martin, D Metcalf and M. Coleman, N. Eng. J. Med., 604 (1992). W. Gunther. Prog. Neuropsychopharmacol. Biol. Psychiatry, Ifl,445 (1992). R.E.Gur, J. Neur.Trans.-G.. 13 (1992). M. Memo, C. Missale. M. Pizzi and P.F. Spano, Clin. Neuropharmacol.,15(Suppl. I), 458A (1992). S.G.Dahl, 0. Edvardsen and I. Sylte, Therapie, 4.6, 453 (1991). I. Penersson and T. Liljefors, J. Med. Chem., 2355 (1992). Y. Machiyama, Schizophr. Bull., B,107 (1992).
m,
m,
z,