The Search for Selective Dopaminergic Autoreceptor Agonists
In the course of a search for new selective dopamine (DA) autoreceptor agonists the DA analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, was resolved into its dextro-(+) and levo-(−) rotatory enantiomers. The compounds were pharmacologically evaluated by means of behavioural and biochemical methods. Surprisingly, both (+)- and (−)-3-PPP show clearcut, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA receptor agonist with activity on autoreceptors as well as postsynaptic receptors, whereas (−)-3-PPP similarly activates DA autoreceptors but, in contrast, concomitantly acts as an antagonist on postsynaptic DA receptors. Moreover, the behavioural/biochemical profile seems to indicate a preferential limbic action for the (−)-enantiomer. Such an action could be explained on the basis of different feedback arrangements in the nigrostriatal and mesolimbic DA systems and it is suggested that compounds such as (−)-3-PPP may find future clinical application as “second-generation” antipsychotic agents, lacking in the debilitating motor side effects produced by drugs in current therapeutic use.
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