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Pramipexole Derivatives as Potent and Selective Dopamine D 3 Receptor Agonists with Improved Human Microsomal Stability

By Jianyong Chen, Cheng Jiang, Beth Levant, Xiaoqin Li, Ting Zhao, Bo Wen, Ruijuan Luo, Duxin Sun and Shaomeng Wang

Abstract

Herein we report the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective agonists of the dopamine‐3 (D 3 ) receptor. A number of these new compounds bind to the D 3 receptor with sub‐nanomolar affinity and show excellent selectivity (>10 000) for the D 3 receptor over the D 1 and D 2 receptors. For example, compound 23 ( N ‐( cis ‐3‐(2‐((( S )‐2‐amino‐4,5,6,7‐tetrahydrobenzo[ d ]thiazol‐6‐yl)(propyl)amino)ethyl)‐3‐hydroxycyclobutyl)‐3‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)benzamide) binds to the D 3 receptor with a K i value of 0.53 n M and shows a selectivity of >20 000 over the D 2 and D 1 receptors in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes. Moreover, in vitro functional assays showed it to be a full agonist for the human D 3 receptor. Fully stable: A series of novel pramipexole derivatives were synthesized by modification of previously reported D 3 ligands. These compounds are much more stable in human microsomes. They retain high affinities for the D 3 receptor and excellent selectivity for D 3 over the D 2 and D 1 receptors. These compounds were determined to be full agonists for the human D 3 receptor

Publisher: WILEY‐VCH Verlag
Year: 2014
DOI identifier: 10.1002/cmdc.201402398
OAI identifier: oai:deepblue.lib.umich.edu:2027.42/109658
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