2,5-Dimethoxy congeners of (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine

• Published in: Journal of medicinal chemistry Vol. 36; no. 16; pp. 2416 - 2419
• Main Authors: Cannon, Joseph G, Kirschbaum, Karen S, Amoo, Victor E. D, Johnson, Alan K, Long, John Paul
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1993
• Subjects: Animals; Bradycardia - chemically induced; Chemistry; Dopamine Agents - analogs & derivatives; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hypotension - chemically induced; Organic chemistry; Piperidines; Preparations and properties; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Vertebrata; Agonist; Mammalia; D2 Dopamine receptor; Cyclization; Ether; Rat; Nitrogen heterocycle; Animal; Six membered ring; Rodentia; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00068a021

p-Dimethoxyaryl analogs of certain potent catechol-derived dopaminergic agonists show dopaminergic properties for which no structure-activity relationship has yet been defined. (S)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine (1, S-"3-PPP") is a dopaminergic autoreceptor agonist, and at high doses it also exhibits postsynaptic antagonism. (R)-1 is a postsynaptic agonist. In a continuation of studies of effects of the p-dimethoxy moiety at dopamine receptors, synthesis and resolution of the 2,5-dimethoxy analog 3 of 3-PPP was undertaken. The two enantiomers and the racemic modification showed cardiovascular effects consistent with actions at DA-2 receptors. The potency of all three compounds was much lower than that of 3-PPP, although they displayed approximately the same duration of action. Absolute configuration does not seem to be a major determinant of these compounds' ability to interact with DA-2 receptors.