SYNTHESIS OF AMINO ACETYLENIC BENZOPHENONE DERIVATIVES AS H3-ANTAGONISTS
Keywords:Amino acetylenic benzophenone derivative, CNS diseases, H3-antagonist activity, Molecular docking
Objective: To synthesize new amino acetylenic benzophenone derivatives with significant H3-antagonist's activity.
Methods: Amino acetylenic benzophenone derivatives were synthesized from the reaction of 2-hydroxybenzophenone with 3-bromoprop-1-in to generate 2-(prop-2-yn-1-yloxy)-1,3-benzophenone (AZ-1). A mixture of 2-(prop-2-yn-1-yloxy)-1,3-benzophenone, paraformaldehyde, cyclic amine, cuprous chloride (catalytic amount) in peroxide free dioane through Mannich reaction yielded the designed amino acetylenic benzophenone derivatives (AZ-2-7).
Results: The IR, H1-NMR, 13C NMR, and elemental analysis were consistent with the assigned structures. The designers of these compounds as H3-antagonists were based on the nationalization of the important criteria that provide effective inhibitory binding with H3-receptor. Molecular docking results of compounds (AZ-2-7) showed a good H3-receptor antagonistic activity relative to thioperamide of-6 (kcal/mol) especially AZ-2 which has-8.6 (kcal/mol).
Conclusion: Docking results provide a good lead to designing more effective H3 antagonists in managing many CNS diseases like Alzheimer, epilepsy, depression, schizophrenia and many others.
Stasiak A, Mussur M, Unzeta M, Lazewska D, Kiec-Kononowicz K, Fogel WA. The central histamine level in rat model of vascular dementia. J Physiol Pharmacol 2011;62(5):549-58.
Borish L. Allergic rhinitis: systemic inflammation and implications for management. J Allergy Clin Immunol 2003;112(6):1021-31.
Quraishi SA, Davies MJ, Craig TJ. Inflammatory responses in allergic rhinitis: traditional approaches and novel treatment strategies. JAOA 2004;104(5 Suppl):7S-15S.
Oh S. Characteristics in molecular vibrational frequency patterns between agonists and antagonists of histamine receptors. Genomics Inf 2012;10(2):128-32.
Hanuskova E, Plevkova J. Histamine and its effects mediated via H3 receptorâ€“potential clinical applications of H3 antagonists. Ammonia 2013;13(Suppl 1):28-36.
Humbert-Claude M, Davenas E, Gbahou F, Vincent L, Arrang JM. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacol 2012;220(1):225-41.
Shi Y, Sheng R, Zhong T, Xu Y, Chen X, Yang D, et al. Identification and Characterization of ZEL-H16 as a novel agonist of the histamine H3 Receptor. PloS One 2012;7(8):e42185.
Motawaj M, Burban A, Davenas E, Arrang JM. Activation of brain histaminergic neurotransmission: a mechanism for cognitive effects of memantine in alzheimer's disease. JPET 2011;336(2):479-87.
Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983;302:832-7.
Kruk M, Miszkiel J, McCreary AC, PrzegaliÅ„ski E, Filip M, BiaÅ‚a G. Effects of the histamine H3 receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice. Pharmacol Rep 2012;64(1316):1316-25.
Sander K, Kottke T, Stark H. Histamine H 3 receptor antagonists go to clinics. Biol Pharm Bull 2008;31(12):2163-81.
Koehler NKU, Stransky E, Shing M, Gaertner S, Meyer M, SchreitmuÂ¨ller, et al. Altered Serum IgG levels to a-synuclein in dementia with lewy bodies and alzheimerâ€™s disease. PloS One 2013;8(5):7-e64649.
Krementsov DN, Wall EH, Martin RA, Subramanian M, Noubade R, Del Rio R, et al. Histamine H3 receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility. PloS One 2013;8(7):e62743.
Vohora D, Bhowmik M. Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci 2012;6:72.
Ellenbroek BA. Histamine H3 receptors. The complex interaction with 57 dopamine and its implications for addiction. BJP 2013;170:46-57.
Guryn R, Staszewski M, WalczyÅ„ski K. Non-imidazole histamine H3 ligands: part V. synthesis and preliminary pharmacological investigation of 1-[2-thiazol-4-yl-and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives. Med Chem Res 2013;1-13.
Lorenzi S, Mor M, Bordi F, Rivara S, Rivara M, Morini G, et al. Validation of a histamine H3receptor model through structureâ€“activity relationships for classical H3antagonists. Bioorg Med Chem 2005;13(19):5647-57.
Sanner MF. Python: a programming language for software integration and development. J Mol Graphics Modell 1999;17(1):57-61.
Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, et al. A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 1984;106(3):765-84.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19(14):1639-62.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. Auto dock 4 and auto dock tools 4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30(16):2785-91.
Maestro, Version 9.2. SchrÃ¶dinger. LLC, New York, NY, USA; 2011.
Jorgensen WL, Tirado-Rives J. The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc 1988;110(6):1657-66.
Gasteiger J, Marsili M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 1980;36(22):3219-28.