New pyridobenzodiazepine derivatives: modifications of the basic side chain differentially modulate binding to dopamine (D(4.2), D(2L)) and serotonin (5-HT(2A)) receptors

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D(4.2), D(2L), and 5-HT(2A) receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido2,3-b]1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido2,3-b]1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K(i) > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D(4.2) and 5-HT(2A) receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity 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 piperidine nucleus as obtained in azabicyclo3.2.1]octane derivatives (23, 38) involved a slight reduction of the affinity at D(4.2) and 5-HT(2A) receptors while the affinity at D(2L) receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D(4.2) receptors but some of these molecules (24, 25, 41) presented a significant 5-HT(2A) binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D(4.2) and 5-HT(2A) affinity (K(i) = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties.