Structural requirements of Na+-dependent antidopaminergic agents: Tropapride, Piquindone, Zetidoline, and Metoclopramide. Comparison with Na+-independent ligands.
Molecular graphic design coupled with PCILO and crystallographic results have been used to investigate the three-dimensional structure of Tropapride, Piquindone, Zetidoline, and Metoclopramide, four dopamine D-2 receptor antagonists showing Na+-dependent binding. Three putative pharmacophoric elements, a nitrogen lone pair, a phenyl ring and a carbonyl moiety, are similarly oriented in all the Na+-dependent drugs. Conversely, for Na+-independent analogs, the two latter pharmacophoric elements play a subordinate role, but two pi-electron regions are systematically localized on the other side of the molecule: the first is a phenyl group while the second is a carbonyl function as in butyrophenones, a cyano group as in R48455, or a phenyl ring as in diphenylbutylpiperidines or tricyclics. The presence of a benzyl ring on this side in Tropapride might explain its weak extrapyramidal effects.
Collin
S
S
Laboratoire de Chimie Moléculaire Structurale, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium.
Vercauteren
D P
DP
Vanderveken
D
D
Evrard
G
G
Durant
F
F
D003196:Computer Graphics; D018492:Dopamine Antagonists; D007093:Imidazoles; D007546:Isoquinolines; D008787:Metoclopramide; D008958:Models, Molecular; D009038:Motion; D009662:Nortropanes; D011954:Receptors, Dopamine / Q000648:ultrastructure; D012964:Sodium; D013329:Structure-Activity Relationship
D018492:Dopamine Antagonists; D007093:Imidazoles; D007546:Isoquinolines; D009662:Nortropanes; D011954:Receptors, Dopamine; C027277:zetidoline; C039413:tropapride; D012964:Sodium; D008787:Metoclopramide; C032412:Ro 22-1319