Propionamide Derivatives as Dual μ‑Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced...

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Veröffentlicht in:Journal of medicinal chemistry 2021-07, Vol.64 (14), p.10139-10154
Hauptverfasser: García, Mónica, Llorente, Virginia, Garriga, Lourdes, Christmann, Ute, Rodríguez-Escrich, Sergi, Virgili, Marina, Fernández, Begoña, Bordas, Magda, Ayet, Eva, Burgueño, Javier, Pujol, Marta, Dordal, Albert, Portillo-Salido, Enrique, Gris, Georgia, Vela, José Miguel, Almansa, Carmen
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Sprache:eng
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Zusammenfassung:A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00417