| Abstract
| - A series of new pyridobenzodiazepines with variation of the basic side chain were synthesizedand evaluated for their binding to D4.2, D2L, and 5-HT2A receptors in comparison with clozapine,haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl groupby a N-phenyl moiety (15−17, 30−32) provided a dramatic decrease of affinity for all receptors(Ki> 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with aN-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D4.2 and 5-HT2Areceptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of theaffinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives(21, 36) possessed less affinity in comparison with the N-methylpiperazine analogues (8, 9)while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidinenucleus as obtained in azabicyclo[3.2.1]octane derivatives (23, 38) involved a slight reductionof the affinity at D4.2 and 5-HT2A receptors while the affinity at D2L receptors was dramaticallyincreased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazinegenerally led to a significant decrease in the affinity for D4.2 receptors but some of thesemolecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a moreflexible side chain induced an increased conformational freedom. Consequently, the preferentialposition of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19with a high D4.2 and 5-HT2A affinity (Ki = 40 and 103 nM, respectively) did not induce catalepticphenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt'stest in mice suggesting antidepressant properties.
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