A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

Mitragynine and 7-hydroxymitragynine
(7OH) are the major alkaloids
mediating the biological actions of the psychoactive plant kratom.
To investigate the structure–activity relationships of mitragynine/7OH
templates, we diversified the aromatic ring of the indole at the C9,
C10, and C12 positions and investigated their G-protein and arrestin
signaling mediated by mu opioid receptors (MOR). Three synthesized
lead C9 analogs replacing the 9-OCH3 group with phenyl
(4), methyl (5), or 3′-furanyl [6 (SC13)] substituents demonstrated partial agonism
with a lower efficacy than DAMGO or morphine in heterologous G-protein
assays and synaptic physiology. In assays limiting MOR reserve, the
G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with
potency similar to morphine without respiratory depression, hyperlocomotion,
constipation, or place conditioning in mice. These results suggest
the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal
antinociception in vivo with reduced opioid liabilities.

帽柱木碱（Mitragynine）与7-羟基帽柱木碱（7-hydroxymitragynine，简称7OH）是介导精神活性植物卡痛（kratom）生物学活性的主要生物碱。为探究帽柱木碱/7-羟基帽柱木碱母核的构效关系，我们对吲哚环的C9、C10及C12位芳香环进行结构修饰，并考察其在μ阿片受体（mu opioid receptors, MOR）介导下的G蛋白与抑制蛋白信号通路活化情况。3种经合成得到的先导C9位衍生物——将9位-OCH3基团分别替换为苯基（化合物4）、甲基（化合物5）及3'-呋喃基[化合物6（SC13）]——在异源G蛋白检测与突触生理学实验中均表现出部分激动活性，其效能低于DAMGO与吗啡。在MOR储备受限的实验体系中，这三种衍生物的G蛋白效能均与丁丙诺啡相当。化合物6（SC13）表现出MOR依赖的镇痛作用，其效价强度与吗啡相近，且在小鼠体内未引发呼吸抑制、运动亢进、便秘或条件性位置偏爱。上述结果表明，在细胞系中轻度激活MOR（G蛋白最大效应百分比Emax≈10%），即可在活体中实现最大化的抗伤害感受效应，同时降低阿片类不良反应风险。