Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP.

S Hjorth, A Carlsson, D Clark, K Svensson, H Wikström, D Sanchez, P Lindberg, U Hacksell, L E Arvidsson, A Johansson

Index: Psychopharmacology 81 , 89-99, (1983)

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Abstract

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.