Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.
Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.
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DOI：
10.1002/prp2.887
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发表时间：
2021-12
影响因子：
2.6
通讯作者：
Clarke WP
中科院分区：
文献类型：
--
作者：
Zamora JC;Smith HR;Jennings EM;Chavera TS;Kotipalli V;Jay A;Husbands SM;Disney A;Berg KA;Clarke WP
阿片类药物过量是美国死亡的主要原因。目前唯一可用的治疗方法是竞争性拮抗剂纳洛酮（Narcan®）。虽然纳洛酮非常有效，并挽救了许多生命，但作为一种竞争性拮抗剂，它有局限性。由于纳洛酮的半衰期较短，如果摄入的阿片类激动剂在体内停留较长时间，则可能发生再硬化。此外，由于纳洛酮的拮抗作用是可以克服的，如果服用相对较大剂量的阿片类激动剂，纳洛酮存在时也可能发生再硬化。在这种情况下，一种长效的、不可克服的拮抗剂可以改善过量治疗。Methocinnamox （MCAM）在体内对mu阿片受体具有长时间的拮抗剂作用。在表达人mu阿片受体的HEK细胞中，MCAM对mu激动剂抑制cAMP产生的拮抗作用是时间依赖性的，不可克服和不可逆的，与（伪）不可逆结合一致。在体内，MCAM局部注射到大鼠后爪，可拮抗mu激动剂介导的热异常性疼痛抑制长达96小时。相比之下，MCAM在HEK细胞和体内对delta或kappa激动剂的拮抗作用与简单的竞争性拮抗一致。令人惊讶的是，在没有受体储备的情况下，MCAM也以配体依赖的方式改变了HEK细胞中mu激动剂的浓度-反应曲线。MCAM对[D‐Ala2，N‐MePhe4，Gly‐ol5]‐脑啡肽（DAMGO）浓度响应曲线的改变对纳洛酮不敏感，这表明除了（伪）不可逆的正构拮抗作用外，MCAM还会变构改变mu激动剂的亲和力和/或内在功效。Methocinnamox （MCAM）是一种（伪）不可逆的，对mu阿片受体具有正构性的拮抗剂。此外，MCAM在激动剂浓度-反应曲线中产生纳洛酮不敏感的变化，这表明MCAM的变构作用改变了mu激动剂的亲和力和/或内在功效。
Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan®). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half‐life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long‐lasting, non‐surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist‐inhibition of cAMP production was time‐dependent, non‐surmountable and non‐reversible, consistent with (pseudo)‐irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist‐mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration‐response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand‐dependent manner. The shift in the [D‐Ala2,N‐MePhe4,Gly‐ol5]‐enkephalin (DAMGO) concentration‐response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)‐irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists. Methocinnamox (MCAM) is a (pseudo‐)irreversible, orthosteric antagonist at mu opioid receptors. In addition, MCAM produces a naloxone insensitive shift in agonist concentration‐response curves which suggests that MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.
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影响因子：
7.3
作者：
Rennison, David;Moynihan, Humphrey;Husbands, Stephen M.
通讯作者：
Husbands, Stephen M.
影响因子：
4.2
作者：
Cano, Manuel;Huang, Ying
通讯作者：
Huang, Ying
影响因子：
6
作者：
Hoots, Brooke;Vivolo-Kantor, Alana;Seth, Puja
通讯作者：
Seth, Puja
影响因子：
3.6
作者：
Jacobs, Blaine A.;Pando, Miryam M.;Berg, Kelly A.
通讯作者：
Berg, Kelly A.
DOI：
10.1124/jpet.110.177493
发表时间：
2011-07-01
影响因子：
3.5
作者：
Berg, Kelly A.;Rowan, Matthew P.;Clarke, William P.
通讯作者：
Clarke, William P.