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

This work was funded by Italian Minister of University and Research project PRIN 2017-201744BN5T. Grant funding (VKA): National Institutes of Health-National Eye Institute-R01EY029409, P30EY00179, National Institutes of Neurological Disorders and Stroke R01NS124784, Unrestricted Grant, Research to Prevent Blindness, New York, NY. This study was partially supported by the Spanish State Research Agency (10.13039/501100011033) under the auspices of MINECO (grant number PID2019-108691RB-I00) and the Andalusian Regional Government (grant CTS109).The design and synthesis of a series of 2,7-diazaspiro[4.4]nonanederivatives as potent sigma receptor (SR) ligands, associated withanalgesic activity, are the focus of this work. In this study, affinitiesat S1R and S2R were measured, and molecular modeling studies wereperformed to investigate the binding pose characteristics. The mostpromising compounds were subjected to in vitro toxicitytesting and subsequently screened for in vivo analgesicproperties. Compound 9d (AD258) exhibitednegligible in vitro cellular toxicity and a highbinding affinity to both SRs (K (i)S1R =3.5 nM, K (i)S2R = 2.6 nM), but not for otherpain-related targets, and exerted high potency in a model of capsaicin-inducedallodynia, reaching the maximum antiallodynic effect at very low doses(0.6-1.25 mg/kg). Functional activity experiments showed thatS1R antagonism is needed for the effects of 9d and thatit did not induce motor impairment. In addition, 9d exhibiteda favorable pharmacokinetic profile.Ministry of Education, Universities and Research (MIUR) PRIN 2017-201744BN5TUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Eye Institute (NEI) R01EY029409, P30EY00179United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) R01NS124784Unrestricted Grant, Research to Prevent Blindness, New York, NYSpanish Government PID2019-108691RB-I00Andalusian Regional Government CTS10