title: 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.
authors.affiliation: Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 (USA). jiachen@umich.edu.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.forename: Beth
authors.initials: B
authors.lastname: Levant
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Luo
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D000077487:Pramipexole; D011485:Protein Binding; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D052160:Benzothiazoles; C000599658:N-(3-(2-((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; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000077487:Pramipexole
keywords: agonists; dopamine-3; microsomal stability; pramipexole derivatives; receptors