On the mode of action of 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, and its enantiomers. With particular reference to dopaminergic mechanisms in the central nervous system

Abstract

As part of an ongoing research project aimed at developing novel selective monoamine-, in particular DA-, receptor active agents the DA analogue 3-PPP, and its enantiomers, were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments revealed clearcut DA autoreceptor-stimulatory properties for all three compounds. In addition, the (+)-enantiomer displayed agonist and the (-)-enantiomer antagonist actions, respectively, on postsynaptic DA receptors. Thus the racemate was rendered a biological profile consonant with selective DA autoreceptor stimulation. Both biochemical and behavioural indices of central DA activity suggested a preferentially limbic impact for racemic 3-PPP and, more interestingly, the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with neuroanatomical differences in the feedback organisation in central (viz. limbic vs. striatal) DA systems. Due to their aforementioned characteristics, it is suggested that compounds like racemic and (-)-3-PPP may find potential clinical utility in the treatment of neuropsychiatric disorders, whilst lacking in the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy. An overview of the literature covering various in vivo and in vitro aspects of 3-PPP pharmacology is also included and taken into consideration, where pertinent. The results suggest that the use of chemical tools like 3-PPP and its enantiomers may provide new insight into central dopaminergic function, e.g. in investigating the consequences of interacting with specific DA receptor populations and the relative importance of pre- vs. postsynaptic feedback regulation in different DA systems, as well as their possible implications.