Work

Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability

Year: 2014

Type: article

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.

Source: ChemMedChem

DOI: 10.1002/cmdc.201402398