This report describes the unique pharmacological profile of FBNTI, a potent DOR antagonist that acts as a MOR agonist via an allosteric mechanism. Binding of FBNTI to opioid receptors expressed in HEK 293 cells revealed a 190-fold greater affinity for DOR (K_i = 0.84 nM) over MOR (K_i = 160 nM). In mice, intrathecal FBNTI produced potent antinociception (ED₅₀ = 46.9 pmol/mouse), which was antagonized by selective MOR antagonists (CTOP, β-FNA). Autoantagonism of the MOR agonism by FBNTI was observed above the ED₇₅ dose, suggesting antagonism of activated MOR. That FBNTI is devoid of agonism in DOR knockout mice is consistent with allosteric activation of the MOR protomer via FBNTI bound to within a MOR–DOR heteromer. This proposed mechanism is supported by calcium mobilization assays, which indicate that FBNTI selectively activates the MOR–DOR heteromer and functionally antagonizes the MOR protomer at >ED₇₅. The unprecedented mode of MOR activation by FBNTI may be responsible for the lack of tolerance after intrathecal (i.t.) administration. FBNTI was highly effective upon topical administration to the ipsolateral hind paw in the Hargreaves assay (EC₅₀ = 0.17 ± 0.08 μM) and without significant contralateral activity, suggesting a lack of systemic exposure.

中文翻译：

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FBNTI，一种 DOR 选择性拮抗剂，可在 MOR-DOR 异构体中变构激活 MOR

本报告描述了 FBNTI 的独特药理学特征，FBNTI 是一种有效的 DOR 拮抗剂，通过变构机制充当 MOR 激动剂。FBNTI 与 HEK 293 细胞中表达的阿片受体的结合揭示了对 DOR ( K _i = 0.84 nM) 的亲和力比 MOR ( K _i = 160 nM) 高190 倍。在小鼠中，鞘内注射 FBNTI 产生有效的镇痛作用（ED ₅₀ = 46.9 pmol/小鼠），可被选择性 MOR 拮抗剂（CTOP、β-FNA）拮抗。在 ED ₇₅以上观察到 FBNTI 对 MOR 激动作用的自身拮抗作用剂量，表明对激活的 MOR 有拮抗作用。FBNTI 在 DOR 敲除小鼠中没有激动作用，这与 MOR 原体通过 FBNTI 结合到 MOR-DOR 异聚体内的变构激活一致。这种提议的机制得到了钙动员测定的支持，这表明 FBNTI 选择性地激活 MOR-DOR 异聚体并在>ED _{75 时}在功能上拮抗 MOR 原聚体。FBNTI 前所未有的 MOR 激活模式可能是鞘内 (it) 给药后缺乏耐受性的原因。FBNTI 在 Hargreaves 试验中对同侧后爪局部给药非常有效 (EC ₅₀ = 0.17 ± 0.08 μM)，并且没有显着的对侧活性，表明缺乏全身暴露。