کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8349913 | 1541817 | 2018 | 23 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
An antidepressant-related pharmacological signature for positive allosteric modulators of α2/3-containing GABAA receptors
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: An antidepressant-related pharmacological signature for positive allosteric modulators of α2/3-containing GABAA receptors An antidepressant-related pharmacological signature for positive allosteric modulators of α2/3-containing GABAA receptors](/preview/png/8349913.png)
چکیده انگلیسی
Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of α2/3-containing GABAA receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of α2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABAA receptor PAMs. A new series of α2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for α2 and α3 constructs over α1 (except KRM-II-82), α4, α5, and α6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that α2/3-selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the α1-preferring antagonist, β-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these α2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Pharmacology Biochemistry and Behavior - Volume 170, July 2018, Pages 9-13
Journal: Pharmacology Biochemistry and Behavior - Volume 170, July 2018, Pages 9-13
نویسندگان
K.R. Methuku, X. Li, R. Cerne, S.D. Gleason, J.M. Schkeryantz, V.V.N.P.B. Tiruveedhula, L.K. Golani, G. Li, M.M. Poe, Md.T. Rahman, J.M. Cook, J.L. Fisher, J.M. Witkin,