The interaction of ammonium, sulfonium, and sulfide analogues of metoclopramide with the dopamine D2 receptor.
A series of permanently charged ammonium and sulfonium analogues of metoclopramide as well as a permanently uncharged sulfide analogue were synthesized and evaluated for their ability to inhibit apomorphine-induced responses on mouse striatal slices. Three of the four permanently charged analogues were found to inhibit apomorphine's effects, although at higher concentrations than either metoclopramide or its dimethyl analogue. In contrast, the sulfide analogue was inactive at concentrations up to 100 microM. These findings are consistent with earlier studies of chlorpromazine and sulpiride analogues and provide further evidence that dopamine antagonists bind in their charged molecular forms to anionic sites on the D2 receptor. Further, the results of this study in conjunction with those of our earlier sulpiride study would seem to indicate that differences in the biological profiles of metoclopramide, a type 1 benzamide useful as a gastric prokinetic agent, and sulpiride, a type 2 benzamide useful for its antipsychotic effects, are not due to any appreciable differences in the binding of the basic nitrogen atom of these molecules.
Harrold
M W
MW
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282.
Sriburi
A
A
Matsumoto
K
K
Miller
D D
DD
Farooqui
T
T
Uretsky
N
N
D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D008787:Metoclopramide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013452:Sulfonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D001549:Benzamides; D000644:Quaternary Ammonium Compounds; D017448:Receptors, Dopamine D2; D013452:Sulfonium Compounds; D008787:Metoclopramide; D001058:Apomorphine