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Synthesis, preliminary pharmacological evaluation and receptor docking studies of 10-amino-3-methoxy-6,8,12,12a-tetrahydro-5H-thiazolo[4',5':4,5]pyrido[2,1-a]isoquinolin-2-ols as novel dopamine D1 receptor inhibitors

Zijun Xiong, Lili Xu, Xuechu Zhen, Wei Fu


A series of 10-amino-6,8,12,12a-tetrahydro-5H-thiazolo[4',5':4,5]pyrido[2,1-a] isoquinolines with substituent hydroxyl or methoxyl groups at C2 and C3 positions of the benzene ring were designed and synthesized. These compounds are 2-aminothiazole bioisosteres of the natural product stepholidine (SPD). Radioligand binding assays showed that compounds 10a, 10b, 10c and 12b had moderate binding affinity and activity for the D1 receptor, as well as high selectivity over the D2 receptor. Among them, 10c exhibited moderate D3 receptor binding affinity. 10a with an amino group in position 10 showed higher affinities toward D3 receptor compared to those without an amino group. In silico docking analysis of active ligands was performed to explain the result of binding assays and analyze structure-activity relationship for further structure optimization. Our analysis suggested that besides the salt bridge interaction formed by the conserved D3.32 with the protonated nitrogen of ligands and the hydrogen bonds formed by S5.42 with 2-hydroxyl group and S5.46 with 3-methoxyl group, a hydrogen bond formed between S188 located on the second extracellular loop (ECL2) and the nitrogen in the thiazole ring was critical to the affinity of this series of compounds for the D1 receptor, which was in agreement with the interaction mode between SPD and the D1 receptor.  Our results suggested that the introduction of thiazole ring changes the pharmacological profile of SPD and the optimized compounds have high selective activity to D1 receptor over D2 receptor. These thiazole-SPD-derivative compounds have potential clinical use in Parkinson’s disease and other conditions related to dopamine receptors.


Dopamine D1 receptor; Bioisosteres of stepholidine; Inhibitory design; Synthesis; Molecular Modeling

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