Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity Dichiara, Maria Ruiz Cantero, María del Carmen González Cano, Rafael Cobos del Moral, Enrique José 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. 2023-09-20T12:29:46Z 2023-09-20T12:29:46Z 2023-08-03 journal article Dichiara, M. et al. Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity. J. Med. Chem. 2023, 66, 16, 11447–11463. [https://doi.org/10.1021/acs.jmedchem.3c00959] https://hdl.handle.net/10481/84530 10.1021/acs.jmedchem.3c00959 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional ACS Publications