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Pramipexole Derivatives as Potent and Selective Dopamine D 3 Receptor Agonists with Improved Human Microsomal Stability
Author(s) -
Chen Jianyong,
Jiang Cheng,
Levant Beth,
Li Xiaoqin,
Zhao Ting,
Wen Bo,
Luo Ruijuan,
Sun Duxin,
Wang Shaomeng
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402398
Subject(s) - pramipexole , dopamine receptor d3 , benzamide , receptor , agonist , chemistry , dopamine receptor d2 , microsome , stereochemistry , dopamine receptor , selectivity , in vitro , biochemistry , pharmacology , biology , medicine , disease , parkinson's disease , catalysis
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.