Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A₁ and A_2A Receptors, and Efficacy in Animal Models of Depression

• Main Authors: Flavia Varano (Author), Daniela Catarzi (Author), Erica Vigiani (Author), Diego Dal Ben (Author), Michela Buccioni (Author), Gabriella Marucci (Author), Lorenzo Di Cesare Mannelli (Author), Elena Lucarini (Author), Carla Ghelardini (Author), Rosaria Volpini (Author), Vittoria Colotta (Author)
• Format: Book
• Published: MDPI AG, 2021-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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) A₁, hA_2A, hA_2B, and hA₃ adenosine receptors (ARs). Several compounds (<b>5</b>, <b>8</b>-<b>10</b>, <b>13</b>, <b>18</b>, <b>19</b>) were characterized by nanomolar and subnanomolar binding affinities for the hA₁ and the hA_2A 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 <b>18</b> (hA₁ K_i = 1.9 nM; hA_2A K_i = 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.

Item Description

10.3390/ph14070657
1424-8247