Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity
Maria Dichiara, Francesca Alessandra Ambrosio, Sang‐Min Lee, M. Carmen Ruiz‐Cantero, Jessica Lombino, Adriana Coricello, Giosuè Costa, Dhara Shah, Giuliana Costanzo, Lorella Pasquinucci, Kyung No Son, Giuseppe Cosentino, Rafael González‐Cano, Agostino Marrazzo, Vinay K. Aakalu, Enrique J. Cobos, Stefano Alcaro, Emanuele Amata
Abstract
High Resolution Image Download MS PowerPoint Slide 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 in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compound 9d ( AD258 ) exhibited negligible in vitro cellular toxicity and a high binding affinity to both SRs ( K i S1R = 3.5 nM, K i 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 9d and that it did not induce motor impairment. In addition, 9d exhibited a favorable pharmacokinetic profile.