4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain.
Mónica GarcíaMarina VirgiliMònica AlonsoCarles AlegretBegoña FernándezAdriana PortRosalia PascualXavier MonroyAlba Vidal-TorresMaría-Teresa SerafiniJosé Miguel VelaCarmen AlmansaPublished in: Journal of medicinal chemistry (2019)
The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.
Keyphrases
- chronic pain
- pain management
- sensitive detection
- reduced graphene oxide
- anti inflammatory
- acinetobacter baumannii
- klebsiella pneumoniae
- escherichia coli
- type diabetes
- ionic liquid
- metabolic syndrome
- binding protein
- visible light
- molecular docking
- spinal cord
- high fat diet induced
- quantum dots
- combination therapy
- tissue engineering
- molecular dynamics simulations