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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Organ Specificity
  • Oxazepines / chemical synthesis*
  • Oxazepines / chemistry
  • Oxazepines / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D4 / agonists
  • Receptors, Dopamine D4 / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT1 Receptor Antagonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Antagonists / chemistry
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Structure-Activity Relationship

Substances

  • 5-(4-methylpiperazin-1-yl)-8-chloropyrido(2,3-b)(1,5)benzoxazepine fumarate
  • Antipsychotic Agents
  • Oxazepines
  • Piperazines
  • Pyridines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-2
  • Receptors, Dopamine D2
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • dopamine D2L receptor
  • Receptor, Serotonin, 5-HT1A
  • Receptors, Dopamine D4