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

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 (KiS1R =
3.5 nM, KiS2R = 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.