Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity. J Med Chem 2023 Aug 24;66(16):11447-11463
Date
08/03/2023Pubmed ID
37535861Pubmed Central ID
PMC10461227DOI
10.1021/acs.jmedchem.3c00959Scopus ID
2-s2.0-85168325923 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
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 EAuthor
Vinay Kumar Aakalu MPH, MD Chair, Professor in the Ophthalmology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnalgesicsHumans
Ligands
Pain
Protein Binding
Receptors, sigma
