I am a
Home I AM A Search Login

Papers of the Week

Papers: 29 Jul 2023 - 4 Aug 2023

2023 Aug 03

J Med Chem


Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity.


Dichiara M, Ambrosio FA, Lee SM, Ruiz-Cantero MC, Lombino J, Coricello A, Costa G, Shah D, Costanzo G, Pasquinucci L, Son KN, Cosentino G, González-Cano R, Marrazzo A, Aakalu VK, Cobos EJ, Alcaro S, Amata E


The design and synthesis of a series of 2,7-diazaspiro[4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics. The most promising compounds were subjected to toxicity testing and subsequently screened for analgesic properties. Compound () exhibited negligible cellular toxicity and a high binding affinity to both SRs (S1R = 3.5 nM, S2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicin-induced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6-1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of and that it did not induce motor impairment. In addition, exhibited a favorable pharmacokinetic profile.