WAY-163909 [(7bR,10aR)-1 ,2,3,4,8,9,10,10a-Octahydro-7ibH-cyclopenta-[ib][1,4]diazepino[6,7,1hi]indole]:A Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Preclinical Antipsychotic-Like Activity

摘要

Serotonin-2C (5-HT_(2C)) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission,with agonists selectively decreasing mesolimbic DA.As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D_2 receptor antagonism,the 5-HT_(2C)-selective receptor agonist,WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1 hi]indole],was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission.Similar to clozapine,WAY-163909 (1.7-30 mg/kg i.p.) decreased apo-morphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy.WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity.WAY-163909 (1.7-17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)-and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice.In conditioned avoidance responding,WAY-163909 (0.3-3 mg/kg i.p.;1-17 mg/kg p.o.) reduced avoidance responding,an effect blocked by the 5-HT_(2B/2C) receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole].WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum.Likewise,in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1-10 mg/kg i.p.).Thus,the profile of the 5-HT_(2C) selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.