化学
伊芬普地尔
吲唑
变构调节
部分
立体化学
NMDA受体
组合化学
受体
生物化学
作者
Judith Lüken,Gunnar Goerges,Nadine Ritter,Paul Disse,Julian A. Schreiber,Judith Schmidt,Bastian Frehland,Dirk Schepmann,Guiscard Seebohm,Bernhard Wünsch
标识
DOI:10.1021/acs.jmedchem.3c01161
摘要
Negative allosteric modulation of GluN2B subunit-containing NMDA receptors prevents overstimulation, resulting in neuroprotective effects. Since the phenol of prominent negative allosteric modulators is prone to rapid glucuronidation, its bioisosteric replacement by an indazole was envisaged. The key step in the synthesis was a Sonogashira reaction of non-protected iodoindazoles with propargylpiperidine derivatives. Modification of the alkynyl moiety allowed the introduction of several functional groups. The synthesized indazoles showed very high GluN2B affinity but limited selectivity over σ receptors. Molecular dynamics simulations revealed the same molecular interactions with the ifenprodil binding site as the analogous phenols. In two-electrode voltage-clamp experiments, enantiomeric 3-(4-benzylpiperidin-1-yl)-1-(1H-indazol-5-yl)propan-1-ols (S)-10a and (R)-10a displayed higher inhibitory activity than ifenprodil. In contrast to phenolic GluN2B antagonists, the indazoles were not conjugated with glucuronic acid. It can be concluded that the phenol of potent GluN2B antagonists can be replaced bioisosterically by an indazole, retaining the high GluN2B affinity and activity but inhibiting glucuronidation.
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