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.
D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D009043:Motor Activity / Q000187:drug effects; D009904:Optical Rotation; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology
D010880:Piperidines; D011954:Receptors, Dopamine; D012110:Reserpine; C026539:preclamol; D001058:Apomorphine; D003913:Dextroamphetamine