阿片受体激动剂研究进展
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摘要
疼痛是机体在受到伤害时的一种反馈而产生令人不快的主观感受,起到警示机体存在实质性或潜在的组织损伤的作用。治疗和缓解疼痛的主要药物是阿片受体激动剂,而传统的阿片受体激动剂存在阿片样副作用(包括成瘾性、耐受性、呼吸抑制性等),从而限制其广泛应用。科研工作者寻找出许多规避副作用的策略,着重介绍在μ-阿片受体激动剂的设计和应用中消除阿片样副作用的传统策略和新型策略,简要介绍κ-阿片受体激动剂的最新研究进展,以期为镇痛药的研发及临床治疗提供新的思路。
Pain is a kind of feedback of body injury which produces unpleasant subjective feelings, alerting the individual of actual or potential tissue damage. The mainstream drugs for the treatment and relief of pain are opioid receptor agonists. However, opioid-like side effects(addiction, tolerance, respiratory depression, etc.) of traditional opioid agonists limit their widespread use. Researchers have developed many effective strategies to avoid the side effects. In this article, the traditional and novel strategies to eliminate opioid side effects during the design and application of μ-opioid receptor agonists were highlighted, and the recent research progress of κ-opioid receptor agonists was briefly introduced, so as to provide new ideas for the development of analgesics and clinical treatment of pain.
Pain is a kind of feedback of body injury which produces unpleasant subjective feelings, alerting the individual of actual or potential tissue damage. The mainstream drugs for the treatment and relief of pain are opioid receptor agonists. However, opioid-like side effects(addiction, tolerance, respiratory depression, etc.) of traditional opioid agonists limit their widespread use. Researchers have developed many effective strategies to avoid the side effects. In this article, the traditional and novel strategies to eliminate opioid side effects during the design and application of μ-opioid receptor agonists were highlighted, and the recent research progress of κ-opioid receptor agonists was briefly introduced, so as to provide new ideas for the development of analgesics and clinical treatment of pain.
引文
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[2]MartinWR,EadesCG,ThompsonJ A,etal.Theeffectsof morphineand nalorphine-like drugs in the nondependent and morphinedependent chronic spinal dose[J]. J Pharmaeol Exp Ther, 1976, 197(3):517-532.
[3]Lord J A, Waterfield A A, Hughes J, et al. Endogenous opioid peptides:multiple agonists and receptors[J]. Nature, 1977, 267(5611):495-499.
[4]Mollereau C, Parmentier M, Mailleux P,et al. ORL1, a novel member oftheopioidreceptorfamily,cloning,functional,expressionand localization[J]. FEBS Let, 1994, 341(1):33-38.
[5]Manchikanti L, Datta S, Smith H S, et al. Future of minimizing opioid adverse effects while maintaining or improving opioid-related analgesia[J]. Therapy, 2009, 6(5):667-683.
[6]CorderG,CastroDC,BruchasMR,etal.Endogenousand exogenous opioids in pain[J]. Annu Rev Neurosci, 2018, 41:453-473.
[7]Crain S M, Shen K F. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasingitsantinociceptivepotencyandattenuatingtolerance/dependenceduringchroniccotreatment[J].ProcNatl AcdSciUSA,1995, 92(23):10540-10544.
[8]ChindaloreVL,CravenR A,YuKP,etal. Addingultralowdosenaltrexonetooxycodoneenhancesandprolongsanalgesia:a randomized, controlled trial of oxytrex[J]. Pain, 2005, 6(6):392-399.
[9]FurstS,RibaP,FriedmannT,etal.Peripheralversuscentral antinociceptiveactionsof6-aminoacid-substitutedderivativesof14-O-methyloxymorphone in acute and inflammatory pain in the rat[J].J Pharmacol Exp Ther, 2005, 312(2):609-618.
[10]KiefferBL.Opioids:firstlessonsfromknockoutmice[J].Trends Phamacol Sci, 1999, 20(1):19-26.
[11]Bailey C P, Connor M. Opioids:cellular mechanisms of tolerance and physical dependence[J]. Curr Opin Pharmacol, 2005, 5(1):60-68.
[12]Nikaido Y, Kurosawa A, Saikawa H, et al. In vivo and in vitro evaluation of novelμ-opioid receptor agonistcompounds.[J]. Eur J Pharmacol,2015, 767:193-200.
[13]HothersallJD, TorellaR,HumphreysS,etal.Residues W320and Y328 within the binding site of the mu-opioid receptor influence opiate ligand bias[J]. Neuropharmacology, 2017, 118:46-58.
[14]Manglik A,Kruse AC,Kobilka TS,etal.Crystalstructureofthe micro-opioidreceptorboundtoamorphinanantagonist[J].Nature,2012, 485(7398):321-326.
[15]Huang W,Manglik A, Venkatakrishnan AJ, etal.Structuralinsights intomicro-opioidreceptoractivation[J].Nature,2015,524(7565):315-321.
[16]DeWire S M, Yamashita D S, Rominger D H, et al. A G protein-biased ligandatthemu-opioidreceptorispotentlyanalgesicwithreduced gastrointestinal and respiratory dysfunction compared with morphine[J].J Pharmacol Exp Ther, 2013, 344(3):708-717.
[17]Schneider S, Provasi D, Filizola M. How oliceridine(TRV-130)binds and stabilizes aμopioid receptor conformational state that selectively triggers G protein signaling pathways[J]. Biochemistry, 2016, 55(46):6456-6466.
[18]ChengJX,Cheng T,Li WH,etal.Computationalinsightsintothe G-protein-biased activation and inactivation mechanisms of theμopioid receptor[J]. Acta Pharmacol Sin, 2018, 39(1):154-164.
[19]Singla N, Minkowitz H S, Soergel D G, et al. A randomized, Phase IIb study investigating oliceridine(TRV130), a novelμ-receptor G-protein pathway selective(μ-GPS)modulator, for the management of moderate to severe acute pain following abdominoplasty[J]. J Pain Res, 2017, 10:2413-2424.
[20]Ok H G, Kim S Y, Lee S J, et al. Can oliceridine(TRV130), an ideal novelreceptor G protein pathway selective(-GPS)modulator, provide analgesia without opioid-related adverse reactions?[J]. Korean J Pain,2018, 31(2):73-79.
[21]Ahmad A A,DavidB,MuchhalaKH,etal.Effectsofacuteand repeated treatment with the biased mu opioid receptor agonist TRV130(oliceridine)on measures of antinociception, gastrointestinal function,and abuse liability in rodents[J]. J Psychopharmacol, 2017, 31(6):730-739.
[22]Schneider S, Provasi D, Filizola M. How Oliceridine(TRV130)binds and stabilizes a mu-opioid receptor conformational state that selectively triggers G protein signaling pathways[J]. Biochemistry, 2016, 55(46):6456-6466.
[23]Wu H, Wacker D, Mileni M, et al. Structure of the human kappa-opioid receptor in complex with JDTic[J]. Nature, 2012, 485(7398):327-332.
[24]Granier S, Manglik A, Kruse A C, et al. Structure of the delta-opioid receptor bound to naltrindole[J]. Nature, 2012, 485(7398):400-404.
[25]Thompson A A,Liu W,ChunE,etal.Structureofthenociceptin/orphanin FQ receptor in complex with a peptide mimetic[J]. Nature,2012, 485(7398):395-399.
[26]Manglik A, Lin H, Aryal D K, et al. Structure-based discovery of opioid analgesics with reduced side effects[J]. Nature, 2016, 537(7619):185-190.
[27]HeinsbroekJ A,Furbish, AB,PetersJ. Asingle,extinction-based treatmentwithakappaopioidreceptoragonistelicitsalong-term reduction in cocaine relapse[J]. Neuropsychopharmacol, 2018, 43(7):1492-1497.
[28]Heins S E, Sorbero M J, Jones C M, et al. High-risk prescribing to medicaid enrollees receiving opioid analgesics:individual-and countylevel factors[J]. Subst Use Misuse, 2018, 53(10):1591-1601.
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[30]Tien Y, Huang W C, Kuo H Y, et al. Pharmacokinetics of dinalbuphine sebacateandnalbuphineinhumanafterintramuscularinjectionof dinalbuphine sebacate in an extended-release formulation[J]. Biopharm Drug Dispos, 2017, 38(8):494-497.