Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2<i>H</i>-pyrrol-2-yl)phosphonates as Imidazoline <i>I</i>₂ Receptor Ligands with Anti-Alzheimer and Analgesic Properties.

ABSTRACT: Imidazoline I₂ receptors (I₂-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I₂-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I₂-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanica

SUBMITTER: Bagan A 

PROVIDER: S-EPMC11831594 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature