偏向性配体——阿片类镇痛药设计新思路
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摘要
吗啡等阿片类药物作为镇痛药应用已有数百年历史,但其致呼吸抑制、耐受和成瘾等副作用限制了该类药物的使用,因此人们一直致力于寻找副作用更低的新型镇痛药。近年研究发现,μ阿片受体下游除了经典的G蛋白依赖型通路外,还独立存在由β-arrestin介导的信号通路,吗啡激活μ阿片受体产生的镇痛、镇静效应主要通过G蛋白依赖型通路介导,而胃肠功能紊乱、呼吸抑制、耐受等副反应则由β-arrestin依赖型通路介导。如果能发现只激活G蛋白依赖型通路而不激活β-arrestin依赖型通路的偏向性配体,就可能得到镇痛效应强而副作用低的化合物,这为设计新型强效、低副作用的阿片类镇痛药提供了新思路。该文将对μ阿片受体下游β-arrestin依赖型信号通路及偏向性配体的发现、发展和应用进行综述。
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.
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.
引文
[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 SHwang,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 M Z,Kuo A,Ghassabian S,et al.Progress in under s tanding 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.
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[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.
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[15]Louis M Luttrell,Robert J Lefkowitz.The role of betaarrestins in the termination and transduction of G-proteincoupled receptor signals[J].J Cell Science,2002,115(Pt3):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.
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[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-arrestindependent 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]Pat r icia H McDonald,Chi-Wing Chow,Will iam EMiller,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 betaarrestins 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,Strachan R T,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 proteincoupled 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 betaarrestin2[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-2determines 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 proteincoupled 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 betaarrestin2in 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 Wde 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].JPharmacology 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 J 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.
[2]Andrew Kolodny,David T Courtwright,Courtwright SHwang,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 M Z,Kuo A,Ghassabian S,et al.Progress in under s tanding 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 P E,Martin W R:The effects of morphine and nalorphine-like drugs in the nondependent,morphinedependent 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-opioidreceptor 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 betaarrestins in the termination and transduction of G-proteincoupled receptor signals[J].J Cell Science,2002,115(Pt3):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-arrestindependent 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]Pat r icia H McDonald,Chi-Wing Chow,Will iam EMiller,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 betaarrestins 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,Strachan R T,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 proteincoupled 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 betaarrestin2[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-2determines 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 proteincoupled 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 betaarrestin2in 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 Wde 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].JPharmacology 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 J 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.