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

Abstract

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, <b>15au</b>, 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, <b>15au</b> showed local, peripheral activity in this test, which was reversed by the σ₁R agonist PRE-084. At equianalgesic doses, <b>15au</b> 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.