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对腺苷A1和A2A受体具有高亲和力且在抑郁症动物模型中有效的新型噻唑并[5,4-d]嘧啶衍生物的设计与合成

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A and A Receptors, and Efficacy in Animal Models of Depression.

作者信息

Varano Flavia, Catarzi Daniela, Vigiani Erica, Dal Ben Diego, Buccioni Michela, Marucci Gabriella, Di Cesare Mannelli Lorenzo, Lucarini Elena, Ghelardini Carla, Volpini Rosaria, Colotta Vittoria

机构信息

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita'degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.

Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.

出版信息

Pharmaceuticals (Basel). 2021 Jul 9;14(7):657. doi: 10.3390/ph14070657.

DOI:10.3390/ph14070657
PMID:34358083
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8308585/
Abstract

New compounds with a 7-amino-2-arylmethyl-thiazolo[5,4-d]pyrimidine structure were synthesized and evaluated in vitro for their affinity and/or potency at the human (h) A, hA, hA, and hA adenosine receptors (ARs). Several compounds (, -, , , ) were characterized by nanomolar and subnanomolar binding affinities for the hA and the hA AR, respectively. Results of molecular docking studies supported the in vitro results. The 2-(2-fluorobenzyl)-5-(furan-2yl)-thiazolo[5,4-d]pyrimidin-7-amine derivative (hA K = 1.9 nM; hA K = 0.06 nM) was evaluated for its antidepressant-like activity in in vivo studies, the forced swimming test (FST), the tail suspension test (TST), and the sucrose preference test (SPT) in mice, showing an effect comparable to that of the reference amitriptyline.

摘要

合成了具有7-氨基-2-芳基甲基-噻唑并[5,4-d]嘧啶结构的新型化合物，并在体外评估了它们对人（h）A、hA、hA和hA腺苷受体（ARs）的亲和力和/或效力。几种化合物（，-，，，）对hA和hA AR的纳摩尔和亚纳摩尔结合亲和力分别进行了表征。分子对接研究结果支持了体外实验结果。在体内研究、小鼠强迫游泳试验（FST）、尾悬测试（TST）和蔗糖偏好试验（SPT）中评估了2-(2-氟苄基)-5-(呋喃-2-基)-噻唑并[5,4-d]嘧啶-7-胺衍生物（hA K = 1.9 nM；hA K = 0.06 nM）的抗抑郁样活性，其效果与参比药物阿米替林相当。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/5bcb07db6517/pharmaceuticals-14-00657-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/66ae31c77c21/pharmaceuticals-14-00657-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/66cfd1549690/pharmaceuticals-14-00657-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/12af3d02158e/pharmaceuticals-14-00657-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/add9a7dc4ed8/pharmaceuticals-14-00657-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/8913ccbd2352/pharmaceuticals-14-00657-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/5bcb07db6517/pharmaceuticals-14-00657-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/66ae31c77c21/pharmaceuticals-14-00657-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/66cfd1549690/pharmaceuticals-14-00657-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/12af3d02158e/pharmaceuticals-14-00657-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/add9a7dc4ed8/pharmaceuticals-14-00657-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/8913ccbd2352/pharmaceuticals-14-00657-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8cb/8308585/5bcb07db6517/pharmaceuticals-14-00657-g004.jpg

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