title: New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.
abstract: A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.
authors.affiliation: Laboratory of Medicinal Chemistry, Drug Research Center, University of Liège , avenue de l'Hôpital 1 (B36), B-4000 Liège 1, Belgium. JF.Liegeois@ulg.ac.be
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
authors.forename: Marine
authors.initials: M
authors.lastname: Deville
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dilly
authors.forename: Cédric
authors.initials: C
authors.lastname: Lamy
authors.forename: Floriane
authors.initials: F
authors.lastname: Mangin
authors.forename: Mélissa
authors.initials: M
authors.lastname: Résimont
authors.forename: Frank I
authors.initials: FI
authors.lastname: Tarazi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009928:Organ Specificity; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000819:agonists / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C441720:5-(4-methylpiperazin-1-yl)-8-chloropyrido(2,3-b)(1,5)benzoxazepine fumarate; D014150:Antipsychotic Agents; D010077:Oxazepines; D010879:Piperazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; C113776:dopamine D2L receptor; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4