Chapter 4 Synthesis and Pharmacological Evaluation of 6-NH2-DPTB and 6-NH2-DPTI, and Related Analogues. Dopamine Receptor Ligands with Free Radical Scavenging Properties as Potential Anti-Parkinson Agents

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindan and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-NH2-DPTB (18, 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5,4-f]-[1]benzopyran) and 6-NH2-DPTI (29, 6-amino-2-(N,N-di-n-propylamino)-thiazolo[4,5-f]indan), and several analogues (19, 24, and 30). The affinity of the DPTBs and DPTIs for DA receptors was evaluated, which revealed 6-NH2-DPTI (29) to have high affinity for DA D3 receptors. In addition, the compounds Chapter 4 90 were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Some compounds were subjected to further pharmacological evaluation in a functional assay (to determine intrinsic activity), in a microdialysis study (to determine effect