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  • Title: Substituted benzamides with conformationally restricted side chains. 2. Indolizidine derivatives as central dopamine receptor antagonists.
    Author: King FD, Hadley MS, McClelland CM.
    Journal: J Med Chem; 1988 Sep; 31(9):1708-12. PubMed ID: 2900897.
    Abstract:
    The substituted benzamides metoclopramide (1) and clebopride (3) are stimulants of gastric motility. They are also central dopamine receptor antagonists with 3 being the more potent. This is presumed to be due to an additional interaction of its N-benzyl group with the receptor. The effect of restricting the conformation of this group by replacing the N-benzylpiperidine side chain of 3 by phenyl-substituted quinolizidines and indolizidines has been investigated. Only the indolizidines had significant activity, the nature of which depended upon the orientation of the phenyl substituent. The 2 alpha-phenyl isomers 5d-h were potent central dopamine D2 receptor antagonists with 5h showing selectivity for the limbic system. The 2 beta-phenyl isomer 5c was a gastric motility stimulant devoid of significant central dopamine receptor antagonist activity. Implications on receptor models are discussed.
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