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-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.
Liégeois
Jean-François
JF
Natural and Synthetic Drugs Research Center, Laboratory of Medicinal Chemistry, University of Liège, avenue de l'Hôpital 1 (B36), Belgium. JF.Liegeois@ulg.ac.be
Eyrolles
Laurence
L
Ellenbroek
Bart A
BA
Lejeune
Christel
C
Carato
Pascal
P
Bruhwyler
Jacques
J
Géczy
Joseph
J
Damas
Jacques
J
Delarge
Jacques
J
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D002460:Cell Line; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C468795:8-chloro-6-(4-phenethyl-1-piperazinyl)-11H-pyrido(2,3-b)(1,4)benzodiazepine; D000588:Amines; D000928:Antidepressive Agents; C493599:DRD4 protein, human; D015259:Dopamine Agents; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; D010879:Piperazines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D018490:Serotonin Agents; C113776:dopamine D2L receptor; D001569:Benzodiazepines; D050638:Receptors, Dopamine D4