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
豆豆完成签到 ,获得积分10
刚刚
展希希发布了新的文献求助10
刚刚
万能图书馆应助缥缈冬寒采纳,获得10
刚刚
vv发布了新的文献求助10
1秒前
汉堡包应助chiweiyoung采纳,获得10
1秒前
3秒前
4秒前
一支布洛芬完成签到,获得积分20
4秒前
4秒前
香蕉觅云应助英俊白莲采纳,获得10
4秒前
英俊的铭应助树精采纳,获得10
6秒前
Ava应助yummy采纳,获得10
6秒前
YJ888发布了新的文献求助10
6秒前
可爱的函函应助lzx采纳,获得10
8秒前
8秒前
gulllluuuukk完成签到,获得积分10
10秒前
Lynn怯霜静完成签到,获得积分10
11秒前
科研通AI5应助青青子衿采纳,获得10
12秒前
孙燕应助lalala采纳,获得50
12秒前
13秒前
13秒前
斯文念波发布了新的文献求助10
14秒前
17秒前
辛某完成签到,获得积分10
17秒前
香蕉觅云应助期刊采纳,获得50
18秒前
18秒前
18秒前
chiweiyoung发布了新的文献求助10
18秒前
无花果应助YJ888采纳,获得10
19秒前
20秒前
20秒前
认真初之发布了新的文献求助10
22秒前
成就茗发布了新的文献求助10
23秒前
一叶舟完成签到 ,获得积分10
23秒前
mm给mm的求助进行了留言
23秒前
Lucas应助KK采纳,获得10
24秒前
25秒前
keyun发布了新的文献求助10
25秒前
25秒前
25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 3989550
求助须知:如何正确求助?哪些是违规求助? 3531774
关于积分的说明 11254747
捐赠科研通 3270278
什么是DOI,文献DOI怎么找? 1804966
邀请新用户注册赠送积分活动 882125
科研通“疑难数据库(出版商)”最低求助积分说明 809176