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 [H-3]spiroperidol was used to evaluate affinity (K-i) of test compounds. Functional activity of selected compounds in stimulating [S-35]GTP gamma S 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 (-)-40 K-i, D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45 K-i, D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC50, 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 (EC50, 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.