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.

中文翻译：

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4-Aryl-1-oxa-4,9-二氮杂螺[5.5]十一烷衍生物作为双μ阿片受体激动剂和σ1受体拮抗剂治疗疼痛。

一个新的系列1-氧杂-4,9-二氮杂螺[5.5]十一烷衍生物作为有效的双配位体为σ-1受体（σ的合成和药理学活性的_1个R）和μ阿片样物质受体（MOR）的报告。使用通用的合成方法探索了使用两种靶药效基团的合并策略设计的中央支架的不同位置。位置9的苯乙基衍生物，位置4的取代吡啶基部分和位置2的小烷基基团提供了最佳轮廓。最好的化合物之一15au具有平衡的双重特性（即MOR激动剂和sigma拮抗作用）和有效的镇痛活性，在小鼠的足爪压力测试中可与MOR激动剂羟考酮媲美。与羟考酮相反，如增加σ所预期₁ - [R拮抗作用，15AU在该试验中，这是由σ反转显示当地，周围活动₁ R激动剂PRE-084。在equianalgesic剂量，15AU显示出比羟考酮便秘少，提供的证据表明，双MOR激动作用和σ ₁ - [R拮抗作用可以是用于获得有效的和更安全的镇痛药的有用策略。