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Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist

Collin, S.
Evrard, G.
Vercauteren, D. P.
Durant, F.
Van de Waterbeemd, Hans
Testa, Bernard
Published in Journal of Medicinal Chemistry. 1989, vol. 32, no. 1, p. 38-42
Abstract A combination of experimental and theoretical methods were used to investigate the stereoelectronic structure of zetidoline, a dopamine D2 receptor antagonist showing Na+-dependent binding. The solid-state conformation of zetidoline is characterized by synplanarity (coplanarity of the two rings with the chloro substituent and the carbonyl group on the same side). The side chain in the crystal adopts a folded conformation which places the azetidine nitrogen atom at about 8 A from the center of the aromatic ring. Quantum mechanical calculations indicate the synperiplanar and antiperiplanar conformations of the ring system to be of approximately equal energies. The molecular electrostatic potential of zetidoline in a nearly extended conformation shows a remarkable similarity with that of orthopramides (e.g. metoclopramide) and indolones (e.g. piquindone), i.e. two groups of drugs displaying the same D2 selectivity and Na+-dependent binding. We postulate that the close stereoelectronic similarity between zetidoline, orthopramides, and indolones accounts for their identical mechanism of action in the molecular level.
Keywords Chemistry, PhysicalImidazolesModels, MolecularMolecular ConformationPhysicochemical PhenomenaReceptors, Dopamine/drug effectsReceptors, Dopamine D2Structure-Activity RelationshipX-Ray Diffraction
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PMID: 2521253

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Deposited on : 2010-08-06

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