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

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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container_end_page 10154
container_issue 14
container_start_page 10139
container_title Journal of medicinal chemistry
container_volume 64
creator 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
description 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.
doi_str_mv 10.1021/acs.jmedchem.1c00417
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title Propionamide Derivatives as Dual μ‑Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain
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