Resolved 3-(3-Hydroxyphenyl)-N-n-propylpiperidine and its analogs: central dopamine receptor activity

Abstract

Seven enantiomeric pairs of N-alkyl analogs of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) were synthesized and evaluated pharmacologically (biochemistry and behavior [in rats]) to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulker than n-propyl. S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors but intrinsic activity at presynaptic receptors only, thus appearing as antagonists at postsynaptic receptors. In the total series, (S)-(.sbd.)-3-PPP ([S]-12) seems to be the most interesting compound both from the theoretical and the therapeutic point of view, possibly attenuating DA function in 2 different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.