Structural, Kinetic, and Pharmacodynamic Mechanisms of d-Amino Acid Oxidase Inhibition by Small Molecules

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• 作者：Seth C. Hopkins ; Michele L. R. Heffernan ; Lakshmi D. Saraswat ; Carrie A. Bowen ; Laurence Melnick ; Larry W. Hardy ; Michael A. Orsini ; Michael S. Allen ; Patrick Koch ; Kerry L. Spear ; Robert J. Foglesong ; Mustapha Soukri ; Milan Chytil ; Q. Kevin Fang ; Steven W. Jones ; Mark A. Varney ; Aude Panatier ; Stephane H. R. Oliet ; Loredano Pollegioni ; Luciano Piubelli ; Gianluca Molla ; Marco Nardini ; Thomas H. Large
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3710-3724
• 全文大小：664K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (K_d 鈮?2鈥? 渭M). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (K_d 鈮?100鈥?00 nM) and slow release kinetics (k < 0.01 s^鈥?) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.