Molecular docking studies (in Schrödinger and Glide software) showed that the molecule m-Cl-BHU (meta-chlorobenzhydrylurea) is complementary to the benzodiazepine binding site of GABAA receptors. Binding energy was low (-11.14 kcal/mol); m-Cl-BHU interacts with the key amino acids at the α1γ2 interface: Tyr159, Tyr209, and H101 Phe77 with high fit to the dG insertion model: 0.741. Binding of [3H]flunitrazepam with the benzodiazepine site of brain GABAA receptors increased in rats with experimental alcoholism treated with m-Cl-BHU at a dose of 100 mg/kg for 14 days. Changes in pharmacokinetic parameters (T1/2, Clt, MRT, MET, and AUC) of the model substrate antipyrine in saliva were seen in healthy volunteers and male patients with alcoholism using Galodif (m-Cl-BHU) at a dose of 300 mg/day for 21 days. Elimination of antipyrine in patients with alcoholism was increased due to activation of microsomal cytochrome P450 in the liver oxidase system.
Similar content being viewed by others
References
T. A. Voronina and S. B. Seredenin, Methodological Recommendations for the Study of Tranquilizer (Anxiolytic) Actions of Pharmacological Substances. Guidelines for Experimental (Preclinical) Study of Novel Pharmacological Substances [in Russian], Remedium, Moscow (2005), pp. 126 – 136.
N. L. Shimanovskii, M. A. Epinetov, and M. Ya. Mel’nikov, Molecular and Nanopharmacology [in Russian], Fizmatlit, Moscow, (2009).
R. Cossart, C. Bernard, and Y. Ben-Ary, Trends Neurosci., No. 2, 108 – 115 (2005).
A. Winkelmann, N. Maggio, J. Eller, et al., J. Clin. Invest., 124, 696 – 711 (2014).
A. Dixon, H. Morris, G. Breen, et al., Proc. Natl. Acad. Sci. USA, 107(5), 2289 – 2294 (2010).
R. W. Olsen and J. Liang, Mol. Brain, 10, 45 (2017).
R. Olsen, Proc. Natl. Acad. Sci. USA, 108(12), 4699 – 4700 (2011).
M. Enoch, Pharmacol. Biochem. Behav., 90(1), 95 – 104 (2008).
S. Roh, S. Matsushita, S. Hara, et al., Alcohol Clin. Exp Res., 35(3), 400 – 407 (2011).
A. Lindemeyer, Y. Shen, and F. Yazdani, Mol. Pharmacol., 92(2), 101 – 12 (2017).
N. A. Bokhan, A. I. Mandel’, S. A. Ivanova, et al., Voprosy Narkol., No. 1, 26 – 62 (2017).
G. F. Koob and N. D. Volkow, Lancet Psychiatry, 3(8), 760 – 773 (2016).
T. V. Shushpanova and A. V. Solonskii, Neurosci. Behav. Physiol., 43, 423 – 430 (2013).
T. V. Shushpanova, J. Alcohol Drug Depend., No. 2, 176 (2014); doi:https://doi.org/10.4172/2329-6488.1000176.
T. V. Shushpanova, A. V. Solonskii, O. V. Shushpanova, Drug Addiction, F. Zhao (ed.), M. Li (coed.), IntechOpen, London, (2018), pp. 73 – 102; doi: https://doi.org/10.5772/intechopen.73333; doi: https://doi.org/10.5772/intechopen.70103.
E. A. Frost, R. S. Gist, and F. Adriano, Int. Anesthesiol. Clin., 49(1), 119 – 133 (2011).
C. Ikonomiou, P. Bittigau, M. J. Ishimaru, et al., Science, 287(5455), 1056 – 1060 (2000).
R. Spanagel, Physiol. Rev., 89(2), 649 – 705 (2009).
S. De Santis, A. Cosa-Linan, R. Garcia-Hernandez, et al., Sci. Adv., 24, 6(26), eaba0154 (2020).
T. V. Shushpanova, Zh. Nevrol. Psikhiat. im. S. S. Korsakova, 7(2), 122 – 124 (1989).
B. Ftsrstera, P. F. Castro, G. Moraga-Cid, and L. G. Aguayo, Front. Cell. Neurosci., 10, 114 (2016); doi: https://doi.org/10.3389/fncel.2016.00114.
G. Addolorato, L. Leggio, F. W. Hopf, et al, Neuropsychopharmacology, 37, 163 – 177 (2012).
J. F. Amundarain, F. Viso Zamarreso, A. Giorgetti, and M. Costabel, J. Biomol. Struct. Dynam., 37(6), 1597 – 1615 (2019).
H. A. Lester, M. I. Dibas, D. S. Dahan, et al, Trends Neurosci., 27, 329 – 336 (2004).
S. M. Sine and A. G. Engel, Nature, 440, 448 – 455 (2006).
T. V. Shushpanova and V. Ya. Semke, Zh. Nevrol. Psikhiat. im. S. S. Korsakova, 106(11), 53 – 56 (2006).
T. V. Shushpanova, A. I. Mandel’, N. A. Bokhan, et al. Yakutskii Med Zh., 4(68), 113 – 117 (2019).
T. V. Shushpanova, N. A. Bokhan, V. F. Lebedeva, et al., J. Addict. Res. Ther., 7(2), 271 (2016).
B. Rikke, K. Kongsbak, P. L. Sshrensen, et al., PLoS One, 8, No. 1 (2013).
T. V. Shushpanova, T. P. Novozheeva, V. Ya. Semke, et al. Russian Patent RU 2155034 C1, August 27, 2000, Application No. 99125063/14 of November 29, 1999.
V. Ya. Semke, T. V. Shushpanova, T. P. Novozheeva, et al., Russian Patent RU 2436573 S2, December 20, 2011, Application No. 2009128808/15 of July 27, 2009.
R. Bergmann, K. Kongsbak, and P. L. Sorensen, PLoS One, 8(1), e52323 (2013).
Schrödinger Release 2017-3: Schrödinger Suite 2017 – 3 Protein Preparation Wizard; Epik, Schrödinger, LLC, New York, NY, 2017; Impact, Schrödinger, LLC, New York, NY, 2017; LigPrep, Schrödinger, LLC, New York, NY, 2017; Prime, Schrödinger, LLC, New York, NY, 2017; QikProp, Schrödinger, LLC, New York, NY (2017).
J. C. Shelley, A. Cholleti, L. L. Frye, et al., J. Comput. Aided Mol. Des., 21, 681 – 691 (2007).
J. L. Friesner, J. L. Banks, R. B. Murphy, et al., J. Med. Chem., 47(7), 1739 – 1749 (2004).
T. A. Halgren, R. B. Murphy, R. A. Friesner, J. Med. Chem., 47(7), 1750 – 1759 (2004).
É. S. Gorshtein, A. V. Semenyuk, and A. Ya. Maiore,” Usp. Gepatol., 14, 128 – 147 (1988).
K. Yamaoka, T. Nakagawa, and T. Uno, J. Pharmacokinet. Biopharm., 6(2), 165 – 175 (1978).
V. K. Piotrovskii, Khim.-Farm. Zh., 18(7), 845 – 849 (1984).
Yu. B. Belousov and K. G. Gurevich, Clinical Pharmacokinetics. The Practice of Substance Dosing [in Russian], Khim.- Farm. Zh., special issue in the Rational Pharmacotherapy series, 54(11), (2005), Littera, Moscow.
G. Zaccara and E. Perucca, Epileptic Disord., 16(4), 409 – 431 (2014).
C. Johannessen Landmark, Expert Rev. Neurother., 10(1), 119 – 140 (2005).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 11, pp. 9 – 16, November, 2020.
Rights and permissions
About this article
Cite this article
Shushpanova, T.V., Bokhan, N.A., Stankevich, K.S. et al. An Innovatory GABA Receptor Modulator and Liver Oxidase System Microsomal Cytochrome P450 Activator in Patients with Alcoholism. Pharm Chem J 54, 1093–1100 (2021). https://doi.org/10.1007/s11094-021-02327-x
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11094-021-02327-x