Agonist‐Dependent Modulation by the Long‐Acting Mu Opioid Receptor Antagonist, Methocinnamox (MCAM)

该死的 敌手 化学 阿片类拮抗剂 兴奋剂 药理学 类阿片 (+)-纳洛酮 μ-阿片受体 竞争对手 阿片受体 受体 医学 生物化学
作者
Hudson R. Smith,Joshua C. Zamora,Teresa A. Chavera,Elaine M. Jennings,Gail Winger,James H. Woods,William P. Clarke,Kelly A. Berg
出处
期刊:The FASEB Journal [Wiley]
卷期号:34 (S1): 1-1 被引量:1
标识
DOI:10.1096/fasebj.2020.34.s1.06832
摘要

Opioid overdose is a leading cause of death in the US. Naloxone (NLX), a mu opioid receptor (MOR) competitive antagonist, is the only treatment currently available for reversing opioid overdose. Unfortunately, NLX’s effects are limited by a short duration of action and ease of surmountability by opioid agonists. Methocinnamox ( MCAM) is a novel MOR antagonist that has a long duration of action in vivo and holds promise as a better treatment for overdose and perhaps opioid use disorder. In this study, we compared the antagonist properties of MCAM to that of NLX and beta‐funaltrexamine (β‐FNA; an irreversible MOR antagonist). In HEK cells that express human MOR, DAMGO inhibited forskolin‐stimulated cAMP levels in a concentration dependent manner with an EC50 of 10 nM and a maximal inhibition of 40%. Pretreatment (15 min or 2 hrs) with NLX (100 nM, 10 x Ki) shifted the DAMGO concentration response curve (CRC) to the right, 100‐fold, in a fully surmountable manner that was independent of pretreatment time and fully reversed following NLX washout. Pretreatment with β‐FNA (10 nM) reduced the DAMGO maximal response in a time‐dependent, non‐surmountable and irreversible manner with no effect on the potency of DAMGO. By contrast to both β‐FNA and NLX, pretreatment with MCAM (10 nM) reduced the maximal response in a time‐dependent, non‐surmountable, non‐washable, and irreversible manner and shifted the DAMGO CRC to the right 1000‐fold. We hypothesized that this rightward shift in the DAMGO CRC may be due to allosteric properties of MCAM at MOR. A hallmark of allosterism is ligand dependence, so we next tested effects of MCAM, β‐FNA and NLX on a different mu opioid agonist, fentanyl. As expected, pretreatment with β‐FNA reduced the maximal response to fentanyl in a non‐surmountable manner without affecting potency, whereas NLX pretreatment shifted the CRC of fentanyl to the right (decreased the potency) in a manner that was fully surmountable and independent of pretreatment time. By contrast, pretreatment with MCAM reduced the maximal response to fentanyl in a non‐surmountable manner and shifted the CRC to the left (increased potency). Altogether, these data suggest that MCAM may be an irreversible orthosteric antagonist and an allosteric modulator at MOR. Support or Funding Information Supported by NIH/NIDA RO1 grant DA048214

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
香蕉觅云应助东晓采纳,获得10
1秒前
1秒前
姜磊完成签到,获得积分20
2秒前
2秒前
xxddw发布了新的文献求助10
3秒前
3秒前
谢海洋完成签到,获得积分10
4秒前
5秒前
loski发布了新的文献求助10
6秒前
7秒前
xueyu发布了新的文献求助10
8秒前
9秒前
lincy完成签到,获得积分10
10秒前
fqk完成签到,获得积分10
10秒前
11秒前
hanleiharry1发布了新的文献求助10
11秒前
11秒前
13秒前
乐乐应助WN采纳,获得10
15秒前
辛勤的刺猬完成签到 ,获得积分10
19秒前
神奇宝贝发布了新的文献求助10
19秒前
19秒前
丘比特应助sssyq采纳,获得10
20秒前
20秒前
芝麻福福完成签到,获得积分10
20秒前
FYm完成签到,获得积分10
21秒前
心灵美孤菱完成签到,获得积分10
21秒前
田様应助阳光怀亦采纳,获得50
22秒前
阿牛哥关注了科研通微信公众号
23秒前
zsl完成签到,获得积分10
25秒前
26秒前
东晓发布了新的文献求助10
26秒前
娴娴完成签到,获得积分10
27秒前
hanleiharry1发布了新的文献求助10
28秒前
乖猫要努力应助pppp采纳,获得10
28秒前
Akim应助坚强的严青采纳,获得10
28秒前
29秒前
29秒前
31秒前
科目三应助旧梦采纳,获得10
31秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989390
求助须知:如何正确求助?哪些是违规求助? 3531487
关于积分的说明 11254109
捐赠科研通 3270153
什么是DOI,文献DOI怎么找? 1804887
邀请新用户注册赠送积分活动 882087
科研通“疑难数据库(出版商)”最低求助积分说明 809174