Structure-activity relationship study of N⁶-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N⁶-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogues: development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization.
In our effort to develop multifunctional drugs against Parkinson's disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [(3)H]spiroperidol was used to evaluate affinity (K(i)) of test compounds. Functional activity of selected compounds in stimulating [(35)S]GTPγS binding was assessed in CHO cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor (for (-)-40K(i), D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45K(i), D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC(50), D2 = 114 nM, D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, nonselective D3 agonist (-)-19 (EC(50), D2 = 2.96 nM and D3 = 1.26 nM) was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model.
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States.
Mark
M
Johnson
Tamara
T
Antonio
Maarten E A
ME
Reith
Aloke K
AK
Dutta
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D005260:Female; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012110:Reserpine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
D016166:Free Radical Scavengers; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; C046649:ropinirole; D012110:Reserpine