Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening DOI Creative Commons
Kristina Puls, Aina-Leonor Olivé-Marti,

Siriwat Hongnak

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(16), С. 13788 - 13801

Опубликована: Авг. 1, 2024

Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential pain, pruritus, and epilepsy, while antagonists depression, anxiety, addiction. The diterpenoid Salvinorin A (SalA), secondary metabolite of Salvia divinorum, potent selective agonist. Unlike typical opioids, SalA lacks basic nitrogen, which encouraged us to search nonbasic ligands. Through structure-based virtual screening using 3D pharmacophore models based on binding mode SalA, we identified novel, nonbasic, potent, agonists. In vitro studies confirmed two hits, SalA-VS-07 SalA-VS-08, as highly showing G protein-biased agonist activity. Both ligands share novel spiro-moiety scaffold. Our findings provide starting points developing therapeutics aimed at pain other conditions in central player.

Язык: Английский

Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening DOI Creative Commons
Kristina Puls, Aina-Leonor Olivé-Marti,

Siriwat Hongnak

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(16), С. 13788 - 13801

Опубликована: Авг. 1, 2024

Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential pain, pruritus, and epilepsy, while antagonists depression, anxiety, addiction. The diterpenoid Salvinorin A (SalA), secondary metabolite of Salvia divinorum, potent selective agonist. Unlike typical opioids, SalA lacks basic nitrogen, which encouraged us to search nonbasic ligands. Through structure-based virtual screening using 3D pharmacophore models based on binding mode SalA, we identified novel, nonbasic, potent, agonists. In vitro studies confirmed two hits, SalA-VS-07 SalA-VS-08, as highly showing G protein-biased agonist activity. Both ligands share novel spiro-moiety scaffold. Our findings provide starting points developing therapeutics aimed at pain other conditions in central player.

Язык: Английский

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