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
antipsychotic agent; JL13; Clozapine; Dopamine D2L and D4 receptors; Serotonin 5-HT1A and 5-HT2A receptors; adrenergic alpha2A receptors; in vitro binding; Receptor Autoradiography; Molecular modeling
Abstract :
[en] A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized in order to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D2L, D4, serotonin 5-HT1A, 5-HT2A and adrenergic 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 multi-receptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar and more flexible side chains are not favourable in this context. 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 D1 and D4 receptors in nucleus accumbens and caudate putamen, and D2 receptors in medial prefrontal cortex and hippocampus while 5 significantly increased D2 and D4 receptors in nucleus accumbens. In addition, 2 increased 5-HT1A and decreased 5-HT2A 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.
Research Center/Unit :
CIRM - Département de pharmacie - Chimie pharmaceutique Harvard Medical School and McLean Hospital - Department of Psychiatry and Neuroscience Program - Boston, USA
Liégeois, Jean-François ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
DEVILLE, Marine ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Laboratoire toxicologie clinique
Dilly, Sébastien ; Université de Liège - ULiège > Département de pharmacie / GIGA-Neurosciences > Chimie pharmaceutique / Pharmacologie
Lamy, Cédric; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Mangin, Floriane; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Résimont, Mélissa; Université de Liège - ULiège > Département de Pharmacie > Chimie pharmaceutique
Tarazi, Frank; Harvard Medical School and McLean Hospital - Boston - USA > Department of Psychiatry and Neuroscience Program
Language :
English
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
Publication date :
2012
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
55
Issue :
1572
Pages :
1582
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Composés antipsychotiques
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique ULg FSR - Université de Liège. Fonds spéciaux pour la recherche
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