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Liegeois JF, Eyrolles L, Ellenbroek BA, Lejeune C, Carato P, Bruhwyler J, Geczy J, Damas J, Delarge J: 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. J Med Chem. 2002 Nov 7;45(23):5136-49.
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-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 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 azabicyclo [3.2.1] 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. |
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