title: Substituted benzamides with conformationally restricted side chains. 2. Indolizidine derivatives as central dopamine receptor antagonists.
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.
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D005769:Gastrointestinal Motility / Q000187:drug effects; D007212:Indolizines / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology; D017448:Receptors, Dopamine D2; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D007212:Indolizines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C014417:clebopride; D008787:Metoclopramide; D001058:Apomorphine