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

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.