Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist

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.

Phenylimidazolidin-2-one Derivatives as Selective 5-HT3 Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT3 Receptor Binding

“…Molecular modeling studies indicated that the molecular electrostatic potential (MEP) of metoclopramide shows a remarkable similarity with that of zetidoline, a potent dopamine D 2 receptor antagonist, in a nearly extended conformation . The close electronic similarity between metoclopramide and zetidoline has been proposed to account for their common D 2 receptor antagonist properties.…”

Stereoelectronic requirements of benzamide 5HT3 antagonists. Comparison with D2 antidopaminergic analogues

“…As we will see later, this equatorial orientation of the basic nitrogen lone pair will explain the 5HT3 profile of compound I . Only one isomer was crystallized from the racemic solution; the C (19) configuration in this isolated isomer is R. 14): H(13)-N(l3)<( 14)-H (14) = 171.4". This conformation leads to a quasi parallel disposition of C( 14)-H ( 14) with the carbonyl function.…”

“…Only one isomer was crystallized from the racemic solution; the C (19) configuration in this isolated isomer is R. 14): H(13)-N(l3)<( 14)-H (14) = 171.4". This conformation leads to a quasi parallel disposition of C( 14)-H ( 14) with the carbonyl function.…”