M4 agonists/5HT7 antagonists with potential as antischizophrenic drugs: serominic compounds

C.J. Suckling, J.A. Murphy, A.I. Khalaf, S. Zhou, D.E. Lizos, A. Nguyen Van Nhien, H. Yasumatsu, A. McVie, L.C. Young, C. McCraw, P.G. Waterman, B.J. Morris, J.A. Pratt, A. Harvey

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Abstract

Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT7 antagonists and M4 agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.
Original languageEnglish
Pages (from-to)2649-2655
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number9
DOIs
Publication statusPublished - 1 May 2007

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Keywords

  • anti-schizophrenic
  • M4 receptor agonist
  • 5HT7 receptor antagonist
  • tetrahydroisoquinolines
  • amidines

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