New pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Liégeois, Jean-François; Eyrolles, L.; Ellenbroek, B. A.et al.
2002 • In Journal of Medicinal Chemistry, 45 (23), p. 5136-5149
[en] 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-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 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-HT2A 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-metbylpiperazine 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-HT2A 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-HT2A 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-HT2A 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.
Disciplines :
Chemistry Pharmacy, pharmacology & toxicology
Author, co-author :
Liégeois, Jean-François ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Eyrolles, L.
Ellenbroek, B. A.
Lejeune, Corinne ; Université de Liège - ULiège > Département des sciences et gestion de l'environnement > Département des sciences et gestion de l'environnement
Carato, P.
Bruhwyler, J.
Geczy, J.
Damas, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Delarge, J.
Language :
English
Title :
New pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Publication date :
07 November 2002
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
Amer Chemical Soc, Washington, United States - Washington
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