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 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-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5,4-f]-[1]benzopyran (<BO>12</BO>) and 6-amino-2-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (<BO>20</BO>) and several analogues (<BO>13</BO>, <BO>17</BO>, and <BO>21</BO>). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound <BO>20</BO> to have high affinity for DA D<INF>3</INF> receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds <BO>12</BO>, <BO>20</BO>, and <BO>21</BO> were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound <BO>20</BO> was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound <BO>20</BO> (GMC 1111) as particularly interesting. Compound <BO>20</BO> caused a rotation activation in unilaterally 6-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<INF>2</INF> receptors. Interestingly, <BO>20</BO> displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.