Development of a Highly Potent D₂/D₃ Agonist and a Partial Agonist from Structure–Activity Relationship Study of <i>N</i>⁶‑(2-(4-(1<i>H</i>‑Indol-5-yl)piperazin-1-yl)ethyl)‑<i>N</i>⁶‑propyl-4,5,6,7-tetrahydrobenzo[<i>d</i>]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

Our structure–activity relationship studies with N6-(2-(4-(1H-indol-5-yl)­piperazin-1-yl)­ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo­[d]­thiazole-2,6-diamine derivatives led to development of a lead compound (−)-21a which exhibited very high affinity (Ki, D2 = 16.4 nM, D3 = 1.15 nM) and full agonist activity (EC50 (GTPγS); D2 = 3.23 and D3 = 1.41 nM) at both D2 and D3 receptors. A partial agonist molecule (−)-34 (EC50 (GTPγS); D2 = 21.6 (Emax = 27%) and D3 = 10.9 nM) was also identified. In a Parkinson’s disease (PD) animal model, (−)-21a was highly efficacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (−)-34 was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (−)-21a was shown to be neuroprotective in protecting neuronal PC12 from toxicity of 6-OHDA. This report, therefore, underpins the notion that a multifunctional drug like (−)-21a might have the potential not only to ameliorate motor dysfunction in PD patients but also to modify disease progression by protecting DA neurons from progressive degeneration.