Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain


Journal of Medicinal Chemistry


Mónica García, Marina Virgili, Mònica Alonso, Carles Alegret, Joan Farran, Begoña Fernández, Magda Bordas, Rosalia Pascual, Javier Burgueño, Alba Vidal-Torres, Antonio R. Fernández de HenestrosaAntonio R. Fernández de Henestrosa, Eva Ayet, Manuel Merlos, Jose Miguel Vela, Carlos R. Plata-Salamán, and Carmen Almansa



The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

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