Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor

The synthesis and dopaminergic activity of a series of C3 and nitrogen-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans (isochromans) is described. The synthesis of the compounds was stereospecific for the 1,3 cis isomer, and the enantioselective synthesis of both enantiomers of one of the analogues (20) was achieved. It was determined that all of the dopaminergic activity resides in the [1R,3S] isomer. Generally, substitution at the C3 position provided compounds with very high potency (less than 10 nm EC50) and selectivity for the D1 receptor, with a wide range of intrinsic activities (60-160%). Analogues containing C3 substituents including aryl, arylalkyl, and cyclic and acyclic alkyl groups showed a marked enhancement of dopaminergic activity compared to the unsubstituted compound. As a class, the drugs were orally active in the rat rotation model with a very long duration of action.