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  • Title: Substituted benzamides with conformationally restricted side chains. 1. Quinolizidine derivatives as selective gastric prokinetic agents.
    Author: Hadley MS, King FD, McRitchie B, Turner DH, Watts EA.
    Journal: J Med Chem; 1985 Dec; 28(12):1843-7. PubMed ID: 4068007.
    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.
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