title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
authors.forename: Laurence
authors.initials: L
authors.lastname: Eyrolles
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ellenbroek
authors.forename: Christel
authors.initials: C
authors.lastname: Lejeune
authors.forename: Pascal
authors.initials: P
authors.lastname: Carato
authors.forename: Jacques
authors.initials: J
authors.lastname: Bruhwyler
authors.forename: Joseph
authors.initials: J
authors.lastname: Géczy
authors.forename: Jacques
authors.initials: J
authors.lastname: Damas
authors.forename: Jacques
authors.initials: J
authors.lastname: Delarge
mesh_terms: 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
chemical_list: 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