Reference : New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
Human health sciences : Psychiatry
Engineering, computing & technology : Computer science
http://hdl.handle.net/2268/109281
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
English
Liégeois, Jean-François mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Deville, Marine [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
Dilly, Sébastien mailto [Université de Liège - ULg > Département de pharmacie / GIGA-Neurosciences > Chimie pharmaceutique / Pharmacologie > >]
Lamy, Cédric [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
Mangin, Floriane [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
Résimont, Mélissa [Université de Liège - ULg > Département de Pharmacie > Chimie pharmaceutique > >]
Tarazi, Frank [Harvard Medical School and McLean Hospital - Boston - USA > Department of Psychiatry and Neuroscience Program > > >]
2012
Journal of Medicinal Chemistry
American Chemical Society
55
1572
1582
Yes (verified by ORBi)
International
0022-2623
1520-4804
Washington
DC
[en] 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
[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.
CIRM - Département de pharmacie - Chimie pharmaceutique ; Harvard Medical School and McLean Hospital - Department of Psychiatry and Neuroscience Program - Boston, USA
F.R.S.-FNRS ; Fonds Spéciaux pour la Recherche de l'Université de Liège
Composés antipsychotiques
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/109281
10.1021/jm2013419

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