Substituted benzamides with conformationally restricted side chains. 1. Quinolizidine derivatives as selective gastric prokinetic agents.
The gastric prokinetic action of metoclopramide may not be primarily due to its dopamine antagonist activity. The present aim was to obtain a selective gastric prokinetic agent lacking dopamine antagonist activity by conformationally restricting the side chain of metoclopramide. In a series of quinolizidinylbenzamides, only compounds with the benzamide moiety at position 2 of the quinolizidine ring retain gastric activity. Of these 2-substituted compounds, the 2 alpha, 9a alpha isomer has potent selective gastric prokinetic activity with only weak dopamine antagonist properties. Spectroscopic data show that the quinolizidine ring preferentially adopts a trans chair-chair conformation with an axial benzamide moiety. However, energy calculations indicate that, at nondopaminergic receptors controlling gastric motility, an alternative cis chair-chair conformation with an equatorial benzamide moiety cannot be ruled out.
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D004298:Dopamine / Q000502:physiology; D018492:Dopamine Antagonists; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D008968:Molecular Conformation; D011312:Pressure; D011807:Quinolizines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D013329:Structure-Activity Relationship
D001549:Benzamides; D018492:Dopamine Antagonists; D011807:Quinolizines; D011954:Receptors, Dopamine; D008787:Metoclopramide; D004298:Dopamine