Conformational analysis of 2-aminoindans and 2-(aminomethyl)indans in relation to their central dopaminergic effects and a dynamic dopamine receptor concept.

ABSTRACT

Conformational analyses on differently substituted 2-aminoindans of significant pharmacological interest were carried out by the molecular mechanics method (MM2). An X-ray structure of (R)-4-methoxy-2-aminoindan has shown the ammonium nitrogen [-)-D-tartaric acid salt) in an axial position. From comparison with other, highly potent, centrally acting dopamine (DA) receptor agonists, it can be predicted that the active enantiomer (R)-4-hydroxy-2-(di-n-propylamino)indan should have its nitrogen atom in an equatorial position. This places it close to the aromatic ring plane, which is one of several prerequisites for potent DA receptor agonism. MM2 correctly calculates (R)-4-methoxy-2-aminoindan and (R)-4-hydroxy-2-(dialkylamino)indan to be more stable in the N-axial and N-equatorial conformations, respectively. Conformational analysis of the dimethyl model compound of the moderately potent dopaminergic phenylpropylamine analogue 4-hydroxy-2-[(di-n-propylamino)methyl]indan was also carried out, in order to see if any conformations of this compound satisfy the requirements for dopaminergic agonism. Two such stable conformations were found.