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

Suckling, C.J. and Murphy, J.A. and Khalaf, A.I. and Zhou, S. and Lizos, D.E. and Nguyen Van Nhien, A. and Yasumatsu, H. and McVie, A. and Young, L.C. and McCraw, C. and Waterman, P.G. and Morris, B.J. and Pratt, J.A. and Harvey, A. (2007) M4 agonists/5HT7 antagonists with potential as antischizophrenic drugs: serominic compounds. Bioorganic and Medicinal Chemistry Letters, 17 (9). pp. 2649-2655. ISSN 0960-894X

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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.