Thiazoloindans and thiazolobenzopyrans: A novel class of orally active central dopamine (partial) agonists

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This app roach has provided dopamine (DA) agonists with good oral availability. To f urther explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-a mino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazole[5,4-f]-[1]benzopyran (12) and 6-amino-2-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (20) and seve ral analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA DQ receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine th eir radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine in trinsic activity. Compound 20 was also studied with microdialysis (to deter mine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesion ed rats (to determine their potential as DA agonists). These studies select ed compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally B-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D-2 receptors. Interes tingly, 20 displayed long-lasting activity and excellent oral availability in B-OH-DA lesioned rats, making this compound potentially useful for the t reatment of Parkinson's disease.