Dual D2 and 5-HT1A Receptors Binding Affinities of 1-Aryl-4-(diarylmethylene)piperazines and Piperidines

U. Ghani1, N. Ullah2,*, S.A. Ali2 and H.A. Al-Muallem2

1Clinical Chemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia

2Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran-31261, Saudi Arabia

*Corresponding author: Fax: +96 63 8604277; Tel: +96 63 8607527, E-mail: nullah@kfupm.edu.sa

Abstract

Although atypical antipsychotics provide significantly greater efficacy against negative symptoms and cognitive deficits of schizophrenia, improvements in negative symptoms and cognition remain modest. The third generation antipsychotics which combine D2 receptor blockade with 5-HT1A receptor activation appear to provide therapeutic benefits against a broader range of symptoms and are essentially free of EPS liability. In an ongoing effort, we have identified new dihydroquinoline, tetrahydroquinoline and methoxyquinoline derivatives of 1-aryl-4-(diarylmethylene)piperazines and 4-aryl-1-(diarylmethylene)piperidines, which are structural analogs of adoprazine (SLV313). The described compounds have been screened for binding affinities of D2 and 5-HT1A receptors. The structure-activity relationship studies indicated that cyclopentenylpyridine, fluorophenylpyridine and cyclopentenylbenzyl groups significantly contribute to the high-binding affinities of these compounds to D2 and 5-HT1A receptors.

Keywords

1-Aryl-4-(diarylmethylene)piperazine, 4-Aryl-1-(diarylmethylene)piperidine, Antipsychotics, D2 and 5-HT1A receptor.

Reference (24)

1.      Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Washington, D.C., edn. 4, Text Revision, p. 297 (2000).

2.      J. Arnt, B. Bang-Andersen, R. Dias and K.P. Bogesø, Drugs Future, 33, 777 (2008); doi:10.1358/dof.2008.033.09.1236966.

3.      S. Kapur, O. Agid, R. Mizrahi and M. Li, NeuroRx, 3, 10 (2006); doi:10.1016/j.nurx.2005.12.003.

4.      P.N. McCormick, S. Kapur, A. Graff-Guerrero, R. Raymond, J.N. Nobrega and A.A. Wilson, Neuropsychopharmacology, 35, 1826 (2010); doi:10.1038/npp.2010.50.

5.      H.Y. Meltzer, Z. Li, Y. Kaneda and J. Ichikawa, Prog. Neuropsychopharmacol. Biol. Psychiatry, 27, 1159 (2003); doi:10.1016/j.pnpbp.2003.09.010.

6.      D.C. Goff and R.I. Shader, in eds.: S.R. Hirsch and D. Weinberger, Non-neurological Side-effects of Antipsychotic Drugs, In: Schizophrenia, Blackwell Publishing, Oxford, UK, pp. 573 (2003).

7.      H.Y. Meltzer, Psychopharmacology, 99(S1), S18 (1989); doi:10.1007/BF00442554.

8.      N.M. Richtand, J.A. Welge, A.D. Logue, P.E. Keck, S.M. Strakowski and R.K. McNamara, in eds.: G. D. Giovanni, V. D. Matteo and E. Esposito, Role of Serotonin and Dopamine Receptor Binding in Antipsychotic Efficacy, In: Serotonin-Dopamine Interaction. Experimental, Clinical and Therapeutic Evidence (Progress in Brain Research), Elsevier BV, Amsterdam, the Netherlands, pp. 155-172 (2008).

9.      A. Newman-Tancredi, D. Cussac and R. Depoortere, Curr. Opin. Investig. Drugs, 8, 539 (2007).

10.  C.A. Jones and A.C. McCreary, Neuropharmacology, 55, 1056 (2008); doi:10.1016/j.neuropharm.2008.05.025.

11.  A. Newman-Tancredi, M.B. Assie, N. Leduc, A.M. Ormiere, N. Danty and C. Cosi, Int. J. Neuropsychopharmacol., 8, 341 (2005); doi:10.1017/S1461145704005000.

12.  M.B. Assie, V. Ravailhe, V. Faucillon and A. Newman-Tancredi, J. Pharmacol. Exp. Ther., 315, 265 (2005); doi:10.1124/jpet.105.087163.

13.  L.A. Bruins Slot, L. De Vries, A. Newman-Tancredi and D. Cussac, Eur. J. Pharmacol., 534, 63 (2006); doi:10.1016/j.ejphar.2006.01.027.

14.  L.A. Bruins Slot, M.S. Kleven and A. Newman-Tancredi, Neuropharmacology, 49, 996 (2005); doi:10.1016/j.neuropharm.2005.05.013.

15.  M.S. Kleven, C. Barret-Grevoz, L.A.B. Slot and A. Newman-Tancredi, Neuropharmacology, 49, 135 (2005); doi:10.1016/j.neuropharm.2005.02.005.

16.  R.A. Bantick, J.F.W. Deakin and P.M. Grasby, J. Psychopharmacol., 15, 37 (2001); doi:10.1177/026988110101500108.

17.  A.C. McCreary, J.C. Glennon, C.R. Ashby Jr., H.Y. Meltzer, Z. Li, J.-H. Reinders, M.B. Hesselink, S.K. Long, A.H. Herremans, H. van Stuivenberg, R.W. Feenstra and C.G. Kruse, Neuropsychopharmacology, 32, 78 (2007); doi:10.1038/sj.npp.1301098.

18.  A. Newman-Tancredi, Curr. Opin. Investig. Drugs, 11, 802 (2010).

19.  S. Cuisiat, N. Bourdiol, V. Lacharme, A. Newman-Tancredi, F. Colpaert and B. Vacher, J. Med. Chem., 50, 865 (2007); doi:10.1021/jm061180b.

20.  N. Ullah, Z. Naturforsch., 67b, 75 (2012); doi:10.5560/ZNB.2012.67b0075.

21.  N. Ullah and A.A.Q. Al-Shaheri, Z. Naturforsch., 67b, 253 (2012); doi:10.5560/ZNB.2012.67b0253.

22.  M. Scarselli, F. Novi, E. Schallmach, R. Lin, A. Baragli, A. Colzi, N. Griffon, G.U. Corsini, P. Sokoloff, R. Levenson, Z. Vogel and R. Maggio, J. Biol. Chem., 276, 30308 (2001); doi:10.1074/jbc.M102297200.

23.  A. Fargin, J.R. Raymond, J.W. Regan, S. Cotecchia, R.J. Lefkowitz and M.G. Caron, J. Biol. Chem., 264, 14848 (1989).

24.  C. Yung-Chi and W.H. Prusoff, Biochem. Pharmacol., 22, 3099 (1973); doi:10.1016/0006-2952(73)90196-2.

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