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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 (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.

SUBMITTER: Chen J

PROVIDER: S-EPMC4277207 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Pramipexole derivatives as potent and selective dopamine D(3) receptor agonists with improved human microsomal stability.

Chen Jianyong J Jiang Cheng C Levant Beth B Li Xiaoqin X Zhao Ting T Wen Bo B Luo Ruijuan R Sun Duxin D Wang Shaomeng S

ChemMedChem 20141022 12

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 ...[more]

PMID: 25338762

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