Troponoids. 7. Chemistry and dopamine agonist activity of ciladopa and related aralkyltroponylpiperazines

A series of N-aralkyltroponylpiperazine derivatives were synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine (DA) pathway and to suppress elevated serum prolactin levels. The compounds were compared to bromocriptine. Some of the more potent analogues were also assayed for their binding affinity to dopamine (DA) and alpha 1-adrenergic receptors. The results established that the potency of some of the compounds were comparable or superior to that of bromocriptine indicated that potent dopaminergic activity was dependent on the presence of both a substituted phenyl and a troponylpiperazine moiety, and confirmed that the dopaminergic activity depends on relative and absolute stereochemistry.