title: Pyridobenzoxazepine and pyridobenzothiazepine derivatives as potential central nervous system agents: synthesis and neurochemical study.
abstract: In order to characterize the pharmacological profile of the different chemical classes of pyridobenzazepine derivatives, a series of N-methylpiperazinopyrido[1,4]- and -[1,5]- benzoxa- and benzothiazepine derivatives were prepared. The affinities for D2, D1, 5-HT2, and cholinergic (M) receptors were measured. In comparison to dibenzazepine reference compounds, a strong decrease of the affinities was observed, less pronounced, however, for the substituted analogues. Oxazepine and thiazepine analogues like clozapine (except 8-chloro-6-(4-methylpiperazin-1-yl)-pyrido[2,3-b][1,4]benzoxazepin e (9) and 8-chloro-6-(4-methylpiperazin-1-yl)pyrido[2,3-b][1,4]- benzothiazepine (11)) were found to be inactive against apomorphine stereotypies. In the open-field test in rats, different molecules showed a high disinhibitory activity as observed with anxiolytic drugs. Moreover, 8-chloro-5-(4-methylpiperazin-1-yl)pyrido[2,3-b][1,5]benzoxazepine (14) presented a clozapine-like profile that was confirmed in the behavioral model in dogs and showed most of the behavioral characteristics described for antipsychotic drugs. Its neurochemical profile, in particular the 5-HT2/D2 ratio, was also compatible with atypical antipsychotic activity.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Liège, Belgium.
authors.forename: J F
authors.initials: JF
authors.lastname: Liégeois
authors.forename: F A
authors.initials: FA
authors.lastname: Rogister
authors.forename: J
authors.initials: J
authors.lastname: Bruhwyler
authors.forename: J
authors.initials: J
authors.lastname: Damas
authors.forename: T P
authors.initials: TP
authors.lastname: Nguyen
authors.forename: M O
authors.initials: MO
authors.lastname: Inarejos
authors.forename: E M
authors.initials: EM
authors.lastname: Chleide
authors.forename: M G
authors.initials: MG
authors.lastname: Mercier
authors.forename: J E
authors.initials: JE
authors.lastname: Delarge
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004285:Dogs; D010077:Oxazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D010077:Oxazepines; D011725:Pyridines; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D013841:Thiazepines