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.
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Liegeois JF, Deville M, Dilly S, Lamy C, Mangin F, Resimont M, Tarazi FI
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.
J Med Chem. 2012 Feb 23;55(4):1572-82. doi: 10.1021/jm2013419. Epub 2012 Feb 13.
- PubMed ID
- 22268448 [ View in PubMed]
- 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 alpha(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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Amoxapine 5-hydroxytryptamine receptor 1A Ki (nM) 221 N/A N/A Details Amoxapine 5-hydroxytryptamine receptor 2A Ki (nM) 1.77 N/A N/A Details Amoxapine Dopamine D4 receptor Ki (nM) 34 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 1A Ki (nM) 101 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 2A Ki (nM) 4.84 N/A N/A Details Clozapine Alpha-2A adrenergic receptor Ki (nM) 185 N/A N/A Details Clozapine Dopamine D4 receptor Ki (nM) 18 N/A N/A Details Loxapine 5-hydroxytryptamine receptor 2A Ki (nM) 2.42 N/A N/A Details Loxapine Dopamine D4 receptor Ki (nM) 9 N/A N/A Details Quetiapine 5-hydroxytryptamine receptor 1A Ki (nM) 125 N/A N/A Details Quetiapine 5-hydroxytryptamine receptor 2A Ki (nM) 101 N/A N/A Details Quetiapine Dopamine D4 receptor Ki (nM) >1000 N/A N/A Details