κ-阿片受体选择性激动剂类镇痛药物研究进展

Advances in κ-opioid receptor selective agonist analgesics

摘要

为了开发更安全有效的新型阿片类镇痛药物,κ-阿片受体 (κ-opioid receptor,KOR) 选择性激动剂因其显著的镇痛效果和避免μ-阿片受体相关的滥用风险而备受瞩目。多肽类药物地非法林 (difelikefalin,商品名为 Korsuva) 的上市为 KOR 选择性激动剂的临床应用开辟了新的领域,更多的小分子和多肽等新化合物的结构和研究策略逐渐受到重视。本文综述了 KOR 激动剂的最新化学进展和面临挑战,并探讨其临床应用和潜在的治疗前景,以期为后续的阿片受体新药设计提供新的选择。

Abstract

To identify safer and more effective opioid analgesics, κ-opioid receptor (KOR) selective agonists have been widely investigated for their potent analgesic properties and lack of the abuse liability typically associated with μ-opioid receptor activation.The clinical approval of the peptide-based drug difelikefalin (Korsuva) established a pivotal milestone, creating new pathways for the therapeutic application of KOR-selective agonists.Subsequently, diverse compound scaffolds, including small molecules and peptides, along with innovative research approaches, have been systematically explored through experimental studies.This review examines the latest chemical advancements and challenges related to KOR agonists, as well as their clinical and potential applications.

关键词

阿片类药物 / 疼痛 / κ-阿片受体 / 选择性激动剂 / 外周作用激动剂 / 镇痛作用

Key words

opioid drugs / pain / κ-opioid receptor / selective agonist / peripheral agonist / analgesic effect

[1] CARLEZON WA Jr,BÉGUIN C,KNOLL AT,et al.Kappa-opioid ligands in the study and treatment of mood disorders[J].Phar-macol Ther,2009,123 (3):334-343.
[2] JANECKA A,FICHNA J,JANECKI T.Opioid receptors and their ligands[J].Curr Top Med Chem,2004,4 (1):1-17.
[3] FREDRIKSSON R,LAGERSTRÖM MC,LUNDIN LG,et al. The G-protein-coupled receptors in the human genome form five main families.Phylogenetic analysis,paralogon groups,and fin-gerprints[J].Mol Pharmacol,2003,63 (6):1256-1272.
[4] RODRÍGUEZ RE.Morphine and microRNA activity:is there a relation with addiction?[J].Front Genet,2012,3: 223.
[5] VOLKOW ND,MCLELLAN AT.Opioid abuse in chronic pain: misconceptions and mitigation strategies5] VOLKOW ND,MCLELLAN AT.Opioid abuse in chronic pain: misconceptions and mitigation strategies[J].N Engl J Med, 2016,374 (13):1253-1263.
[6] CHE T,MAJUMDAR S,ZAIDI SA,et al.Structure of the nanobody-stabilized active state of the kappa opioid receptor[J]. Cell,2018,172 (1-2):55-67.e15.
[7] GRUDT TJ,WILLIAMS JT.Kappa-Opioid receptors also in-crease potassium conductance[J].Proc Natl Acad Sci USA, 1993,90 (23):11429-11432.
[8] RUSIN KI,GIOVANNUCCI DR,STUENKEL EL,et al.Kappa-opioid receptor activation modulates Ca2+currents and secretion in isolated neuroendocrine nerve terminals[J].J Neurosci, 1997,17 (17):6565-6574.
[9] BRUCHAS MR,LAND BB,CHAVKIN C.The dynorphin/kap-pa opioid system as a modulator of stress-induced and pro-addic-tive behaviors[J].Brain Res,2010,1314:44-55.
[10] BRUCHAS MR,MACEY TA,LOWE JD,et al.Kappa opioid receptor activation of p38 MAPK is GRK3-and arrestin-depend-ent in neurons and astrocytes[J].J Biol Chem,2006, 281 (26):18081-18089.
[11] BRUCHAS MR,YANG T,SCHREIBER S,et al.Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase[J]. J Biol Chem,2007,282 (41):29803-29811.
[12] MCLENNAN GP,KISS A,MIYATAKE M,et al.Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta-arrestin 2-dependent MAPK-mediated pathways[J].J Neuro-chem,2008,107 (6):1753-1765.
[13] CAMILLERI M.Novel pharmacology:asimadoline,a kappa-opi-oid agonist,and visceral sensation[J].Neurogastroenterol Motil, 2008,20 (9):971-979.
[14] BELCHEVA MM,CLARK AL,HAAS PD,et al.Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes[J].J Biol Chem,2005,280 (30):27662-27669.
[15] CLARK CR,BIRCHMORE B,SHARIF NA,et al.PD117302: a selective agonist for the kappa-opioid receptor[J].Br J Phar-macol,1988,93 (3):618-626.
[16] LAHTI RA,MICKELSON MM,MCCALL JM,et al.3H U-69593 a highly selective ligand for the opioid kappa receptor[J]. Eur J Pharmacol,1985,109 (2):281-284.
[17] HUNTER JC,LEIGHTON GE,MEECHAM KG,et al.CI-977, a novel and selective agonist for the kappa-opioid receptor[J]. Br J Pharmacol,1990,101 (1):183-189.
[18] LAHTI RA,VONVOIGTLANDER PF,BARSUHN C.Properties of a selective kappa agonist,U-50,488H[J].Life Sci,1982, 31 (20-21):2257-2260.
[19] LIU-CHEN L,HUANG P.Signaling underlying kappa opioid re-ceptor-mediated behaviors in rodents[J].Front Neurosci,2022, 16: 964724.
[20] CHE T,DWIVEDI-AGNIHOTRI H,SHUKLA AK,et al.Bi-ased ligands at opioid receptors:current status and future direc-tions[J].Sci Signal,2021,14 (677):eaav0320.
[21] MACHELSKA H,CELIK MÖ.Advances in achieving opioid an-algesia without side effects[J].Front Pharmacol,2018,9: 1388.
[22] BRUST TF,MORGENWECK J,KIM SA,et al.Biased agonists of the kappa opioid receptor suppress pain and itch without cau-sing sedation or Dysphoria[J].Sci Signal,2016, 9 (456): ra117.
[23] FAOUZI A,VARGA BR,MAJUMDAR S.Biased opioid ligands[J].Molecules,2020,25 (18):E4257.
[24] ENDOH T,TAJIMA A,IZUMIMOTO N,et al.TRK-820,a se-lective kappa-opioid agonist,produces potent antinociception in Cynomolgus monkeys[J].Jpn J Pharmacol,2001,85 (3): 282-290.
[25] SUZUKI T,IZUMIMOTO N,TAKEZAWA Y,et al.Effect of re-peated administration of TRK-820,a kappa-opioid receptor ago-nist,on tolerance to its antinociceptive and sedative actions[J]. Brain Res,2004,995 (2):167-175.
[26] ENDOH T,MATSUURA H,TAJIMA A,et al.Potent antinoci-ceptive effects of TRK-820,a novel kappa-opioid receptor agonist[J].Life Sci,1999,65 (16):1685-1694.
[27] KUMAGAI H,EBATA T,TAKAMORI K,et al.Efficacy and safety of a novel κ-agonist for managing intractable pruritus in di-alysis patients[J].Am J Nephrol,2012,36 (2):175-183.
[28] WIKSTRÖM B,GELLERT R,LADEFOGED SD,et al.Kappa-opioid system in uremic pruritus:multicenter,randomized, double-blind,placebo-controlled clinical studies[J].J Am Soc Nephrol,2005,16 (12):3742-3747.
[29] KUMAGAI H,EBATA T,TAKAMORI K,et al.Effect of a no-vel kappa-receptor agonist,nalfurafine hydrochloride,on severe itch in 337 haemodialysis patients:a Phase III,randomized, double-blind,placebo-controlled study[J].Nephrol Dial Trans-plant,2010,25 (4):1251-1257.
[30] ONA XB,COMAS DR,URRÚTIA G.Opioids for acute pancre-atitis pain[J].Cochrane Database Syst Rev,2013,2013 (7): CD009179.
[31] KEATING GM.Nalmefene:a review of its use in the treatment of alcohol dependence[J].CNS Drugs,2013,27 (9):761-772.
[32] DUNN AD,REED B,ERAZO J,et al.Signaling properties of structurally diverse kappa opioid receptor ligands:toward in vitro models of in vivo responses[J].ACS Chem Neurosci,2019, 10 (8):3590-3600.
[33] EGEDE JO,AJAH LO,UMEORA OU,et al.Pentazocine alone versus pentazocine plus diclofenac for pain relief in the first 24 hours after Caesarean section:a randomized controlled study[J]. J Clin Diagn Res,2017,11 (4):QC01-QC05.
[34] DORTCH-CARNES J,POTTER DE.Bremazocine:a kappa-opi-oid agonist with potent analgesic and other pharmacologic proper-ties[J].CNS Drug Rev,2005,11 (2):195-212.
[35] SPETEA M,SCHMIDHAMMER H.Kappa opioid receptor lig-ands and pharmacology:diphenethylamines,a class of structural-ly distinct,selective kappa opioid ligands[J].Handb Exp Phar-macol,2022,271:163-195.
[36] ALBERT-VARTANIAN A,BOYD MR,HALL AL,et al.Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?[J].J Clin Pharm Ther,2016,41 (4):371-382.
[37] SCHMIDHAMMER H,ERLI F,GUERRIERI E,et al.Develop-ment of diphenethylamines as selective kappa opioid receptor lig-ands and their pharmacological activities[J].Molecules,2020, 25 (21): 5092.
[38] SPETEA M,BERZETEI-GURSKE IP,GUERRIERI E,et al. Discovery and pharmacological evaluation of a diphenethylamine derivative (HS665),a highly potent and selective κ opioid re-ceptor agonist[J].J Med Chem,2012, 55 (22): 10302-10306.
[39] SPETEA M,EANS SO,GANNO ML,et al.Selective κ receptor partial agonist HS666 produces potent antinociception without in-ducing aversion after i.c.v.administration in mice[J].Br J Pharmacol,2017,174 (15):2444-2456.
[40] ERLI F,GUERRIERI E,BEN HADDOU T,et al.Highly po-tent and selective new diphenethylamines interacting with the κ-opioid receptor:synthesis,pharmacology,and structure-activity relationships[J].J Med Chem,2017,60 (17):7579-7590.
[41] ZHOU L,LOVELL KM,FRANKOWSKI KJ,et al.Development of functionally selective,small molecule agonists at kappa opioid receptors[J].J Biol Chem,2013,288 (51):36703-36716.
[42] DOOLEY CT,NY P,BIDLACK JM,et al.Selective ligands for the mu,delta,and kappa opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial li-brary[J].J Biol Chem,1998,273 (30):18848-18856.
[43] VANDERAH TW,LARGENT-MILNES T,LAI J,et al.Novel D-amino acid tetrapeptides produce potent antinociception by se-lectively acting at peripheral kappa-opioid receptors[J].Eur J Pharmacol,2008,583 (1):62-72.
[44] BINDER W,MACHELSKA H,MOUSA S,et al.Analgesic and antiinflammatory effects of two novel kappa-opioid peptides[J]. Anesthesiology,2001,94 (6):1034-1044.
[45] ARENDT-NIELSEN L,OLESEN AE,STAAHL C,et al.Anal-gesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal,multi-tissue experimen-tal human pain model:selective effect on visceral pain[J].Anes-thesiology,2009,111 (3):616-624.
[46] BECK TC,REICHEL CM,HELKE KL,et al.Non-addictive o-rally-active kappa opioid agonists for the treatment of peripheral pain in rats[J].Eur J Pharmacol,2019,856: 172396.
[47] FUGAL J,SERPA SM.Difelikefalin:a new κ-opioid receptor agonist for the treatment of hemodialysis-dependent chronic kid-ney disease-associated pruritus[J].Ann Pharmacother,2023, 57 (4):480-488.
[48] FISHBANE S,JAMAL A,MUNERA C,et al.A phase 3 trial of difelikefalin in hemodialysis patients with pruritus[J].N Engl J Med,2020,382 (3):222-232.
[49] CHAVKIN C,JAMES IF,GOLDSTEIN A.Dynorphin is a spe-cific endogenous ligand of the kappa opioid receptor[J].Science, 1982,215 (4531):413-415.
[50] SCHLECHTINGEN G,DEHAVEN RN,DAUBERT JD,et al.Structure-activity relationships of dynorphin a analogues modified in the address sequence[J].J Med Chem,2003,46 (11): 2104-2109.
[51] ALDRICH JV,MCLAUGHLIN JP.Peptide kappa opioid receptor ligands:potential for drug development[J].AAPS J,2009, 11 (2):312-322.
[52] BRUGOS B,ARYA V,HOCHHAUS G.Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tol-erant rats:effect of different routes of administration[J].AAPS J,2004,6 (4):e36.
[53] ALDRICH JV,KULKARNI SS,SENADHEERA SN,et al.Un-expected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208[J].Chem Med Chem, 2011,6 (9):1739-1745.
[54] DE MARCO R,BEDINI A,SPAMPINATO S,et al.Versatile picklocks to access all opioid receptors:tuning the selectivity and functional profile of the cyclotetrapeptide c[phe-d-pro-phe-trp] (CJ-15,208) [J].J Med Chem,2016,59 (19):9255-9261.
[55] BEDINI A,DI CESARE MANNELLI L,MICHELI L,et al. Functional selectivity and antinociceptive effects of a novel KOPr agonist[J].Front Pharmacol,2020,11: 188.
[56] MURATSPAHIĆ E,DEIBLER K,HAN JM,et al.Design and structural validation of peptide-drug conjugate ligands of the kap-pa-opioid receptor[J].Nat Commun,2023,14 (1): 8064.