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Published on: October 4, 2021
Pramipexole derivatives as potent and selective dopamine D(3) receptor agonists with improved human microsomal
Jianyong Chen1, Cheng Jiang, Beth Levant
1Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 (USA). jiachen@umich.edu.
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 (D3 ) receptor. A number of these new compounds bind to the D3 receptor with sub-nanomolar affinity and show excellent selectivity (>10,000) for the D3 receptor over the D1 and D2 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 D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20,000 over the D2 and D1 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 D3 receptor.
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