WAY 163969 A 5HT2C Agonist Treatment for Schizophrenia

The 5-HT2C-selective receptor agonist, WAY-163909 [12][1,4]diazepino[12] indole],was reported to be active in various animal models of schizophrenia (Marquis et al. 2007). At doses of 1.7-30 mg/kg IP, it decreased apomorphine-induced climbing and behaved like an atypical in that it did not cause catalepsy. Similar to 5-HT2A antagonists, e.g., M100907, WAY 163909 (0.3-3 mg/kg subcutaneous [SC]) was reported to be more effective in inhibiting PCP-induced locomotor activity than d-amphetamine with no effect on spontaneous activity. WAY 163909 (1.7 to 17 mg/kg IP) 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. Like all known antipsychotic drugs, WAY 163909 reduced conditioned-avoidance responding, an effect blocked by the 5-HT2B/2C receptor antagonist SB 206553. At very high doses, WAY 163909 (10 mg/kg SC) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. It showed some selectivity in targeting DA neurons in the ventral tegmental area, sparing the substantia nigra with both acute and chronic (21-day) administration. WAY 163909 was recently reported to augment the ability of haloperidol or clozap-ine to block apomorphine-induced climbing behavior in mice without enhancing catalepsy (Grauer et al. 2009a). It also potentiated the ability of both antipsychotic drugs to block avoidance responses, suggesting that WAY 163909 might be useful as adjunctive treatment for schizophrenia, similar to what has been postulated for the 5-HT2A inverse agonist pimavanserin (Grauer et al. 2009b). These effects were attributed to the ability of 5-HT2C agonism to selectively suppress DA release in the nucleus accumbens and inhibit the firing of DA neurons in the ventral tegmentum, sparing the striatum and the substantia nigra. These unique results are very suggestive of efficacy in schizophrenia, but only clinical testing can verify the potential of what would truly be a new generation of antipsychotic agents.

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