Synthesis and Pharmacological Evaluation of Thiazole and Isothiazole Derived Apomorphines

Abstract

We have presented the synthesis of novel thiazolo- and isothiazolo-apomorphines 12-17 resulting-in part-from an unexpected isomerization step occurred during the acid-catalyzed rearrangement of precursor thiazolo-morphinandienes 3-5. These 2,3-disubstituted apomorphines represent a new group of A-ring substituted aporphines. The receptor binding studies revealed that with the exception of two derivatives all the tested compounds have limited affinity for dopamine-receptor subtypes. Functional calcium assay for the most active isothiazolo-apomorphine showed higher affinities for D(1) and D(2L) subtypes. The docking of these ligands has been modelled to human D(2) and D(3 )receptors. On the basis of the predicted models, we identified an important cation-p interaction for the binding of isothiazolo-apomorphine 16.