Development of 1,3-thiazole analogues of imidazopyridines as potent positive allosteric modulators of GABAA receptors

Development of 1,3-thiazole analogues of imidazopyridines as potent positive allosteric modulators of GABAA receptors Full article

Journal

Bioorganic Chemistry
ISSN: 1090-2120 , E-ISSN: 0045-2068

Output data

Year: 2020, Volume: 94, Article number : 103334, Pages count : DOI: 10.1016/j.bioorg.2019.103334

Authors

Tikhonova Tatyana A. ¹ , Rassokhina Irina V. ¹ , Kondrakhin Eugeny A. ² , Fedosov Mikhail A. ¹ , Bukanova Julia V. ³ , Rossokhin Alexey V. ³ , Sharonova Irina N. ³ , Kovalev Georgy I. ² , Zavarzin Igor V. ¹ , Volkova Yulia A. ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russia
2	V. V. Zakusov Institute of Pharmacology, Russian Academy of Sciences, 8 Baltiyskaya Str., 125315 Moscow, Russia
3	Research Center of Neurology, 5 By-str. Obukha, 105064 Moscow, Russia

Structure–activity relationship studies were conducted in the search for 1,3-thiazole isosteric analogs of imidazopyridine drugs (Zolpidem, Alpidem). Three series of novel γ-aminobutyric acid receptor (GABAAR) ligands belonging to imidazo[2,1-b]thiazoles, imidazo[2,1-b][1,3,4]thiadiazoles, and benzo[d]imidazo[2,1-b]thiazoles were synthesized and characterized as active agents against GABAAR benzodiazepine-binding site. In each of these series, potent compounds were discovered using a radioligand competition binding assay. The functional properties of highest-affinity compounds 28 and 37 as GABAAR positive allosteric modulators (PAMs) were determined by electrophysiological measurements. In vivo studies on zebrafish demonstrated their potential for the further development of anxiolytics. Using the OECD “Fish, Acute Toxicity Test” active compounds were found safe and non-toxic. Structural bases for activity of benzo[d]imidazo[2,1-b]thiazoles were proposed using molecular docking studies. The isosteric replacement of the pyridine nuclei by 1,3-thiazole, 1,3,4-thiadiazole, or 1,3-benzothiazole in the ring-fused imidazole class of GABAAR PAMs was shown to be promising for the development of novel hypnotics, anxiolytics, anticonvulsants, and sedatives drug-candidates.

Tikhonova T.A. , Rassokhina I.V. , Kondrakhin E.A. , Fedosov M.A. , Bukanova J.V. , Rossokhin A.V. , Sharonova I.N. , Kovalev G.I. , Zavarzin I.V. , Volkova Y.A.
Development of 1,3-thiazole analogues of imidazopyridines as potent positive allosteric modulators of GABAA receptors
Bioorganic Chemistry. 2020. V.94. 103334 . DOI: 10.1016/j.bioorg.2019.103334 WOS Scopus OpenAlex

≡ Web of science:	WOS:000505596300005
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