<strong>Biased Ligand——Novel Paradigm for Opioid Analgesics</strong>

Abstract

Abstract:Morphine and related opioids have been used as clinical analgesics for centuries，but various side effects-which include respiratory depression，tolerance and addictionset a limit to medication. Consequently，unremitting efforts have been directed towards the discovery of effective and nonlethal pain killers. Recent studies identified a novel β-arrestindependent pathway through μ-opioid receptor and indicated that side effects of morphine are mediated through β-arrestin-dependent pathway while G-protein-dependent pathway is thought to confer analgesia，which means biased ligands to G-protein signaling are possible analgesics without side effects. The theory of biased ligands may provide a novel strategy to design better and safer opioid analgesics. In this review，we summarized the discovery，development and application of β-arrestin-dependent pathway and biased ligands.

Key words:biased ligands,&,mu,opioid receptor,signal transduction,analgesic

CLC Number:

R964

SUN Yi，TAN Bo，SU Rui-bin.Biased Ligand——Novel Paradigm for Opioid Analgesics[J]. Acta Neuropharmacologica, 2018, 8(2): 1-7.

References

【1】 Thompson G L, Kelly E, Christopoulos A, et al. Novel GPCR paradigms at the mu-opioid receptor[J]. J British pharmacology, 2015, 172(2):287-296.

【2】 Andrew Kolodny, David T Courtwright, Courtwright S Hwang, et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction[J]. Annual Review of Public Health, 2015, 36:559-574.

【3】 Imam MZ, Kuo A, Ghassabian S, et al. Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression[J]. Neuropharmacology, 2017, 131:238-255.

【4】 Richard G Frank, Harold A Pollack. Addressing the fentanyl threat to public health[J]. J New England Medicine, 2017, 376(7):605-607.

【5】 Nora D Volkow, A Thomas McLellan. Opioid abuse in chronic pain--misconceptions and mitigation strategies[J].J New England Medicine, 2016, 374(13):1253-1263.

【6】 Gavril W Pasternak. Opioids and their receptors: Are we there yet? [J]. Neuropharmacology 2014, 76 Pt B:198-203.

【7】 Hughes J, Smith T W, Kosterlitz H W, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity[J]. Nature, 1975, 258(5536): 577-580.

【8】 Gilbert PE, Martin WR: The effects of morphine and nalorphine-like drugs in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog[J]. J Pharmacology and Experimental Therapeutics, 1976, 198(1):66-82.

【9】 Hans W D Matthes, Rafael Maldonado, Frederic Simonin, et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene[J]. Nature, 1996, 383(6603):819-823.

【10】 Jonathan D Violin, Aimee L Crombie, David G Soergel, et al. Biased ligands at G-protein-coupled receptors: promise and progress[J]. Trends in Pharmacological Sciences, 2014, 35(7):308-316.

【11】 Huang Wei-jiao, Aashish Manglik, A J Venkatakrishnan, et al. Structural insights into micro-opioid receptor activation[J]. Nature, 2015, 524(7565):315-321.

【12】 Attramadal H, Arriza J L, Aoki C, et al. Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family[J]. J Biological Chemistry, 1992, 267(25):17882-17890.

【13】 Oakley R H, Laporte S A, Holt J A, et al. Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors[J]. J Biological Chemistry, 2000, 275(22):17201-17210.

【14】 Yuri K Peterson, Louis M Luttrell. The diverse roles of arrestin scaffolds in g protein-coupled receptor signaling[J]. Pharmacological Reviews, 2017, 69(3):256-297.

【15】 Louis M Luttrell, Robert J Lefkowitz. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals[J]. J Cell Science, 2002, 115(Pt 3): 455-465.

【16】 Kirsten M Raehal, Laura M Bohn. beta-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia[J]. Handbook of Experimental Pharmacology, 2014, 219:427-443.

【17】 Reddy Peera Kommaddi, Sudha K Shenoy. Arrestins and protein ubiquitination[J]. Progress in Molecular Biology and Translational Science, 2013, 118:175-204.

【18】 McDonald P H, Lefkowitz R J. Beta-Arrestins: new roles in regulating heptahelical receptors' functions[J]. Cellular Signalling, 2001, 13(10):683-689.

【19】 Laporte S A, Oakley R H, Zhang J, et al. The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis[J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96(7):3712-3717.

【20】 Sudha K Shenoy. Seven-transmembrane receptors and ubiquitination[J]. Circulation research 2007, 100(8):1142-1154.

【21】 Sudha K Shenoy, Xiao Kun-hong, Vidya Venkataramanan, et al. Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor[J]. J Biological Chemistry, 2008, 283(32):22166-22176.

【22】 Luttrell L M, Ferguson S S, Daaka Y, et al. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes[J]. Science (New York, NY), 1999, 283(5402):655-661.

【23】 Erik G Strungs, Louis M Luttrell. Arrestin-dependent activation of ERK and Src family kinases[J]. Handbook of Experimental Pharmacology, 2014, 219:225-257.

【24】 Gong Kai-zheng, Li Zi-jian, Xu Ming, et al. A novel protein kinase A-independent, beta-arrestin-1-dependent signaling pathway for p38 mitogen-activated protein kinase activation by beta2-adrenergic receptors[J]. J Biological Chemistry, 2008, 283(43): 29028-29036.

【25】 Patricia H McDonald, Chi-Wing Chow, William E Miller, et al. A receptor-regulated MAPK scaffold for the activation of JNK3[J]. Science (New York, NY), 2000, 290(5496):1574-1577.

【26】 Pierce K L, Lefkowitz R J: Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors[J]. Nature Reviews Neuroscience, 2001, 2(10):727-733.

【27】 Samama P, Cotecchia S, Costa T, et al. A mutation-induced activated state of the beta 2-adrenergic receptor[J]. Extending the ternary complex model. The Biological Chemistry, 1993, 268(7):4625-4636.

【28】 Kenakin T. Agonist-receptor efficacy. II. Agonist trafficking of receptor signals[J]. Trends in Pharmacological Sciences, 1995, 16(7):232-238.

【29】 Dean P Staus DP, Strachan RT, Manglik A, et al. Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation[J]. Nature, 2016, 535(7612):448-452.

【30】 Manglik A, Kruse A C. Structural basis for g protein-coupled receptor activation[J]. 2017, 56(42):5628-5634.

【31】 Terry P Kenakin, Arthur Christopoulos. Signalling bias in new drug discovery: detection, quantification and therapeutic impact[J]. Nature Reviews Drug discovery, 2013, 12(3):205-216.

【32】 Kelly E. Efficacy and ligand bias at the mu-opioid receptor[J]. British J Pharmacology, 2013, 169(7):1430-1446.

【33】 Laura M Bohn, Robert J Lefkowitz, Raul R Gainetdinov, et al. Enhanced morphine analgesia in mice lacking beta-arrestin 2[J]. Science (New York, NY), 1999, 286(5449): 2495-2498.

【34】 Laura M Bohn, Raul R Gainetdinov, Lin Fang-Tsyr, et al. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence[J]. Nature, 2000, 408(6813):720-723.

【35】 Laura M Bohn, Robert J Lefkowitz, Marc G Caron. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice[J]. The J Neuroscience : Official J Society for Neuroscience, 2002, 22(23):10494-10500.

【36】 Bohn L M, Gainetdinov R R, Caron M G. G protein-coupled receptor kinase/beta-arrestin systems and drugs of abuse: psychostimulant and opiate studies in knockout mice[J]. Neuromolecular Medicine 2004, 5(1):41-50.

【37】 Kirsten M Raehal, Laura M Bohn. The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics[J]. Neuropharmacology, 2011, 60(1):58-65.

【38】 Barhara Przewlocka, Agnieszka Sieja, Katarzyna Starowicz, et al. Knockdown of spinal opioid receptors by antisense targeting beta-arrestin reduces morphine tolerance and allodynia in rat[J]. Neuroscience Letters, 2002, 325(2):107-110.

【39】 Cullen Schmid, Nicole M Kennedy, Nicolette C Ross, et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics[J]. Cell, 2017, 171(5):1165-1175.e1113.

【40】 Zhou X Edward, He Yuan-zheng, Parker W de Waal, et al. Identification of phosphorylation codes for arrestin recruitment by g protein-coupled receptors[J]. Cell, 2017, 170(3):457-469.e413.

【41】 Scott M DeWire, Dennis S Yamashita, David H Rominger, et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine[J]. J Pharmacology Experimental Therapeutics, 2013, 344(3):708-717.

【42】 Neil Singla, Harold S Minkowitz, David G Soergel, et al. A randomized, Phase IIb study investigating oliceridine (TRV130), a novel micro-receptor G-protein pathway selective (mu-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty[J]. J Pain Research, 2017, 10:2413-2424.

【43】 Aashish Manglik, Lin Henry, Dipendra Aryal, et al. Structure-based discovery of opioid analgesics with reduced side effects[J]. Nature, 2016, 537(7619):185-190.

【44】 Neil Burford, Traynor J R, Alt A. Positive allosteric modulators of the mu-opioid receptor: a novel approach for future pain medications[J]. British journal of pharmacology 2015, 172(2):277-286.

【45】 Martin C Michel, Steven J Charlton. Biased agonism in drug discovery - is it too soon to choose a path? [J]. Molecular Pharmacology, 2018, 93(4):mol.117.110890.

[1]	LIU Xuan, TENG Jin-liang.Effect of Dexmedetomidine on Perioperative Analgesia[J]. Acta Neuropharmacologica, 2019, 9(6): 41-46.
[2]	ZHAO Peng-hui，PANG Ce，ZHEN Pan.A New Idea to Treat Glioma with Mulberin[J]. Acta Neuropharmacologica, 2019, 9(5): 44-49.
[3]	王奇.Bushen-Yizhi Formula Inhibits the NLRP3/NFκB Mediated Neuroinflammation and Improves the Motor Dysfunction in a Mouse Model of Parkinson's Disease[J]. Acta Neuropharmacologica, 2018, 8(5): 71-72.
[4]	LIN Zhi-bin.Pharmacological Progress of Ganoderma on Anti-aging and Anti-Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2018, 8(1): 9-15.
[5]	ZAN Gui-ying，SUN Xiang，LI Qing-lin，LIU Jing-gen.Research Progress of the Role and Underlying Mechanism of Dynorphin/κ Opioid Receptor in the Development of Depression[J]. Acta Neuropharmacologica, 2018, 8(1): 54-64.
[6]	WANG Bao-lei，WANG Jia，GUO Chun-yan.Study on Antithrombotic Mechanism Based on Platelet Pathway[J]. Acta Neuropharmacologica, 2017, 7(5): 34-38.
[7]	WAN Ye，GUO Chun-yan，LI Yong-min.Research Progress of Traditional Chinese Medicine in Parkinson’s Disease[J]. Acta Neuropharmacologica, 2017, 7(4): 36-42.
[8]	TIAN You，WANG Xue，AI Jing.Research Progress of Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2017, 7(4): 53-64.
[9]	ZHANG Li-hang， YIN Ming.Thinking of Influences of Small Molecules on Neural Stem Cell Neurogenesis[J]. Acta Neuropharmacologica, 2017, 7(1): 1-9.
[10]	LUO Piao，CHU Shi-feng，CHEN Nai-hong.Progress on Adipokines Participating in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2017, 7(1): 45-52.
[11]	SUN Zhi-hua，LUO Su-lan.Nicotinic Acetylcholine Receptors and Diseases[J]. Acta Neuropharmacologica, 2017, 7(1): 53-64.
[12]	GAO Jin-chao， ZHAO Wen-juan， YIN Ming.Progress in the Relationship of Apolipoprotein E4 on Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2016, 6(6): 31-39.
[13]	WANG Lin-fang，HUANG Shu-bing，XU Yi-da，CUI Chun，SHEN Yan-qin.Effects of Loganin on MPTP-Induced Autophagy in PC12 Cells[J]. Acta Neuropharmacologica, 2016, 6(5): 14-21.
[14]	SU Xiao-mei，ZHANG Dan-shen.Advances of Targeted Drug Delivery Based on PEG-PCL[J]. Acta Neuropharmacologica, 2016, 6(5): 22-28.
[15]	DU Guan-tao，ZHANG Chun-teng，HONG Hao.Progress on Research of 5-Lipoxygenase in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2016, 6(5): 39-44.

Biased Ligand——Novel Paradigm for Opioid Analgesics

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles15

Recommended Articles

Metrics