Indolizidine and quinolizidine derivatives of the dopamine autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP).
Eight indolizidine and quinolizidine derivatives of 3-PPP were synthesized and tested for possible dopamine (DA) autoreceptor activity. The equatorial indolizidine derivative 19e had the profile of a selective autoreceptor agonist and was half as active as 3-PPP. However, resolution of the compound revealed that the 8R enantiomer was an unselective DA agonist with a profile similar to (+)-3-PPP, while the 8S enantiomer was a weak DA antagonist without any DA agonist activity. The unsaturated quinolizidine derivative 21 also had the profile of a DA antagonist while the axial quinolizidine derivative 18a had an amphetamine-like profile in 6-OHDA-lesioned rats. All other derivatives were inactive. The observed structure-activity relationships were in agreement with existing DA receptor models, although these models are not apparently detailed enough to explain why the 8S enantiomer of 19e is inactive as a DA agonist.
D000818:Animals; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D019805:alpha-Methyltyrosine
D007202:Indicators and Reagents; D008781:Methyltyrosines; D010880:Piperidines; D011954:Receptors, Dopamine; D019805:alpha-Methyltyrosine; D012110:Reserpine; C026539:preclamol