Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism:WLB-73502,an analgesic with improved efficacy and safety profile compared to strong opioids

作     者：Alba Vidal-Torres Begoña Fernández-Pastor Mónica García Eva Ayet Anna Cabot Javier Burgueño Xavier Monroy Bertrand Aubel Xavier Codony Luz Romero Rosalía Pascual Maria Teresa Serafini Gregorio Encina Carmen Almansa Daniel Zamanillo Manuel Merlos JoséMiguel Vela 

作者机构：WeLab BarcelonaParc Cientific de BarcelonaBarcelona 08028Spain 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第1期

页      面：82-99页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the Centre for the Development of Industrial Technology(Centro para el Desarrollo Tecnológico Industrial CDTI),references IDI-20130943 and IDI20150915(Spain) 

主　　题：WLB-73502 Sigma-1 receptor Mu-opioid receptor Biased agonist Analgesic activity Chronic pain Neuropathic pain Safety 

摘      要：Opioids are the most effective painkillers,but their benefit-risk balance often hinder their therapeutic ***-73502 is a dual,bispecific compound that binds sigma-1(S1R)and mu-opioid(MOR)***-73502 is an antagonist at the *** behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificantβ-arrestin-2 recruitment,thus demonstrating low intrinsic efficacy on MOR at both signalling *** its partial MOR agonism,WLB-73502exerted full antinociceptive efficacy,with potency superior to morphine and similar to oxycodone against nociceptive,inflammatory and osteoarthritis pain,and superior to both morphine and oxycodone against neuropathic ***-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive *** to morphine and oxycodone,tolerance to its antinociceptive effect did not develop after repeated 4-week ***,contrary to opioid comparators,WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy,and it was devoid of proemetic effect(retching and vomiting)in ferrets at potentially effective ***-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.