title: Substituted benzamides with conformationally restricted side chains. 1. Quinolizidine derivatives as selective gastric prokinetic agents.
abstract: 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.
mesh_terms: 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
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D011807:Quinolizines; D011954:Receptors, Dopamine; D008787:Metoclopramide; D004298:Dopamine