(+)-UH 232 and (+)-UH 242: Novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors

Abstract

The (+)- and (−)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series ofin vivo biochemical and behavioral experiments. These studies showed that the (+)- and (−)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (−)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (−)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (−)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+)-forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission),e.g. in geriatric practice.