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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Mini-Review Article

Aiming at Ideal Therapeutics-MOPr/DOPr or MOPr-DOPr Heteromertargeting Ligand

Author(s): Wakako Fujita*

Volume 20, Issue 31, 2020

Page: [2843 - 2851] Pages: 9

DOI: 10.2174/1568026620666200423095231

Price: $65

Abstract

Background and Objective: The recent alarming reports related to “opioid crisis” necessitate the development of safer and effective analgesics without unwanted side effects. Thus, there needs to be an alternative target or strategy for the development of drugs for the treatment of opioid use/abuse. As one of the novel targets, in these two decades, ligands targeting opioid receptor “heteromerization” including mu-opioid receptor (MOPr)-delta opioid receptor (DOPr) heteromer have been proposed and the pharmacological advancement of reduced side effects has been broadly accepted and well recognized. In this review, some of the ligands targeting both MOPr and DOPr or MOPr-DOPr heteromers are introduced especially focusing on their pharmacological effects in vivo.

Conclusion: It has been found that most of those ligands possess potent antinociceptive activity (as much as or higher than that of morphine) with reduced side effects such as tolerance. In addition, some of them are also able to reduce or prevent physiological withdrawal symptoms observed under chronic opioid use. Importantly, there are an increasing number of evidence that show changes in heteromer expression in various pathological animal models and these strongly argue for targeting heteromers for the development of the next generation of pain medication in the near future.

Keywords: MOPr-DOPr Heteromer, Antinociception, Less tolerance, Peptidic, Non-peptidic, Bivalent, Small molecule.

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[1]
Volkow, N.D.; Collins, F.S. The role of science in addressing the opioid crisis. N. Engl. J. Med., 2017, 377(4), 391-394.
[http://dx.doi.org/10.1056/NEJMsr1706626] [PMID: 28564549]
[2]
Schmid, C.L.; Kennedy, N.M.; Ross, N.C.; Lovell, K.M.; Yue, Z.; Morgenweck, J.; Cameron, M.D.; Bannister, T.D.; Bohn, L.M. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell, 2017, 171, 1165-1175.e1113.
[http://dx.doi.org/10.1016/j.cell.2017.10.035]
[3]
Miyamoto, Y.; Portoghese, P.S.; Takemori, A.E. Involvement of delta 2 opioid receptors in the development of morphine dependence in mice. J. Pharmacol. Exp. Ther., 1993, 264(3), 1141-1145.
[PMID: 8383738]
[4]
Bilsky, E.J.; Bernstein, R.N.; Hruby, V.J.; Rothman, R.B.; Lai, J.; Porreca, F. Characterization of antinociception to opioid receptor selective agonists after antisense oligodeoxynucleotide-mediated “knock-down” of opioid receptor in vivo. J. Pharmacol. Exp. Ther., 1996, 277(1), 491-501.
[PMID: 8613959]
[5]
Kest, B.; Lee, C.E.; McLemore, G.L.; Inturrisi, C.E. An antisense oligodeoxynucleotide to the delta opioid receptor (DOR-1) inhibits morphine tolerance and acute dependence in mice. Brain Res. Bull., 1996, 39(3), 185-188.
[http://dx.doi.org/10.1016/0361-9230(95)02092-6] [PMID: 8866695]
[6]
Zhu, Y.; King, M.A.; Schuller, A.G.; Nitsche, J.F.; Reidl, M.; Elde, R.P.; Unterwald, E.; Pasternak, G.W.; Pintar, J.E. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron, 1999, 24(1), 243-252.
[http://dx.doi.org/10.1016/S0896-6273(00)80836-3] [PMID: 10677041]
[7]
Günther, T.; Dasgupta, P.; Mann, A.; Miess, E.; Kliewer, A.; Fritzwanker, S.; Steinborn, R.; Schulz, S. Targeting multiple opioid receptors - improved analgesics with reduced side effects? Br. J. Pharmacol., 2018, 175(14), 2857-2868.
[http://dx.doi.org/10.1111/bph.13809] [PMID: 28378462]
[8]
Ugur, M.; Derouiche, L.; Massotte, D. Heteromerization modulates mu opioid receptor functional properties in vivo. Front. Pharmacol., 2018, 9, 1240.
[http://dx.doi.org/10.3389/fphar.2018.01240] [PMID: 30483121]
[9]
Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H.H.; Pintar, J.E.; Devi, L.A. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc. Natl. Acad. Sci. USA, 2004, 101(14), 5135-5139.
[http://dx.doi.org/10.1073/pnas.0307601101] [PMID: 15044695]
[10]
Wang, D.; Sun, X.; Bohn, L.M.; Sadée, W. Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Mol. Pharmacol., 2005, 67(6), 2173-2184.
[http://dx.doi.org/10.1124/mol.104.010272] [PMID: 15778451]
[11]
Golebiewska, U.; Johnston, J.M.; Devi, L.; Filizola, M.; Scarlata, S. Differential response to morphine of the oligomeric state of μ-opioid in the presence of δ-opioid receptors. Biochemistry, 2011, 50(14), 2829-2837.
[http://dx.doi.org/10.1021/bi101701x] [PMID: 21361347]
[12]
Rozenfeld, R.; Devi, L.A. Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta opioid receptor heterodimers. FASEB J., 2007, 21(10), 2455-2465.
[http://dx.doi.org/10.1096/fj.06-7793com] [PMID: 17384143]
[13]
George, S.R.; Fan, T.; Xie, Z.; Tse, R.; Tam, V.; Varghese, G.; O’Dowd, B.F. Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J. Biol. Chem., 2000, 275(34), 26128-26135.
[http://dx.doi.org/10.1074/jbc.M000345200] [PMID: 10842167]
[14]
Charles, A.C.; Mostovskaya, N.; Asas, K.; Evans, C.J.; Dankovich, M.L.; Hales, T.G. Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory. Mol. Pharmacol., 2003, 63(1), 89-95.
[http://dx.doi.org/10.1124/mol.63.1.89] [PMID: 12488540]
[15]
Gupta, A.; Mulder, J.; Gomes, I.; Rozenfeld, R.; Bushlin, I.; Ong, E.; Lim, M.; Maillet, E.; Junek, M.; Cahill, C.M.; Harkany, T.; Devi, L.A. Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci. Signal., 2010, 3(131), ra54.
[http://dx.doi.org/10.1126/scisignal.2000807] [PMID: 20647592]
[16]
Erbs, E.; Faget, L.; Scherrer, G.; Matifas, A.; Filliol, D.; Vonesch, J.L.; Koch, M.; Kessler, P.; Hentsch, D.; Birling, M.C.; Koutsourakis, M.; Vasseur, L.; Veinante, P.; Kieffer, B.L.; Massotte, D. A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct. Funct., 2015, 220(2), 677-702.
[http://dx.doi.org/10.1007/s00429-014-0717-9] [PMID: 24623156]
[17]
Fujita, W.; Gomes, I.; Dove, L.S.; Prohaska, D.; McIntyre, G.; Devi, L.A. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem. Pharmacol., 2014, 92(3), 448-456.
[http://dx.doi.org/10.1016/j.bcp.2014.09.015] [PMID: 25261794]
[18]
Derouiche, L.; Ugur, M.; Pierre, F.; Mann, A.; Doridot, S.; Ory, S.; Schulz, S.; Massotte, D. Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking. ; , 2018. (Pre Print)
[http://dx.doi.org/10.1101/455147]
[19]
Tiwari, V.; He, S.Q.; Huang, Q.; Liang, L.; Yang, F.; Chen, Z.; Tiwari, V.; Fujita, W.; Devi, L.A.; Dong, X.; Guan, Y.; Raja, S.N. Activation of micro-delta opioid receptor heteromers inhibits neuropathic pain behavior in rodents. Pain, 2019. (ePub ahead of Print)
[20]
Daniels, D.J.; Lenard, N.R.; Etienne, C.L.; Law, P.Y.; Roerig, S.C.; Portoghese, P.S. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc. Natl. Acad. Sci. USA, 2005, 102(52), 19208-19213.
[http://dx.doi.org/10.1073/pnas.0506627102] [PMID: 16365317]
[21]
Aceto, M.D.; Harris, L.S.; Negus, S.S.; Banks, M.L.; Hughes, L.D.; Akgün, E.; Portoghese, P.S. MDAN-21: A bivalent opioid ligand containing mu-agonist and delta-antagonist pharmacophores and its effects in rhesus monkeys. Int. J. Med. Chem., 2012, 2012327257
[http://dx.doi.org/10.1155/2012/327257] [PMID: 25954526]
[22]
Lee, Y.S.; Kulkarani, V.; Cowell, S.M.; Ma, S.W.; Davis, P.; Hanlon, K.E.; Vanderah, T.W.; Lai, J.; Porreca, F.; Vardanyan, R.; Hruby, V.J. Development of potent μ and δ opioid agonists with high lipophilicity. J. Med. Chem., 2011, 54(1), 382-386.
[http://dx.doi.org/10.1021/jm100982d] [PMID: 21128594]
[23]
Schiller, P.W.; Fundytus, M.E.; Merovitz, L.; Weltrowska, G.; Nguyen, T.M.; Lemieux, C.; Chung, N.N.; Coderre, T.J. The opioid mu agonist/delta antagonist DIPP-NH(2)[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J. Med. Chem., 1999, 42(18), 3520-3526.
[http://dx.doi.org/10.1021/jm980724+] [PMID: 10479285]
[24]
Balboni, G.; Guerrini, R.; Salvadori, S.; Bianchi, C.; Rizzi, D.; Bryant, S.D.; Lazarus, L.H. Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties. J. Med. Chem., 2002, 45(3), 713-720.
[http://dx.doi.org/10.1021/jm010449i] [PMID: 11806723]
[25]
Salvadori, S.; Trapella, C.; Fiorini, S.; Negri, L.; Lattanzi, R.; Bryant, S.D.; Jinsmaa, Y.; Lazarus, L.H.; Balboni, G. A new opioid designed multiple ligand derived from the micro opioid agonist endomorphin-2 and the delta opioid antagonist pharmacophore Dmt-Tic. Bioorg. Med. Chem., 2007, 15(22), 6876-6881.
[http://dx.doi.org/10.1016/j.bmc.2007.08.047] [PMID: 17851080]
[26]
Balboni, G.; Fiorini, S.; Baldisserotto, A.; Trapella, C.; Sasaki, Y.; Ambo, A.; Marczak, E.D.; Lazarus, L.H.; Salvadori, S. Further studies on lead compounds containing the opioid pharmacophore Dmt-Tic. J. Med. Chem., 2008, 51(16), 5109-5117.
[http://dx.doi.org/10.1021/jm800587e] [PMID: 18680274]
[27]
Salvadori, S.; Fiorini, S.; Trapella, C.; Porreca, F.; Davis, P.; Sasaki, Y.; Ambo, A.; Marczak, E.D.; Lazarus, L.H.; Balboni, G. Role of benzimidazole (Bid) in the delta-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH(2)-Bid (UFP-502). Bioorg. Med. Chem., 2008, 16(6), 3032-3038.
[http://dx.doi.org/10.1016/j.bmc.2007.12.032] [PMID: 18178091]
[28]
Jinsmaa, Y.; Marczak, E.D.; Balboni, G.; Salvadori, S.; Lazarus, L.H. Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph. Pharmacol. Biochem. Behav., 2008, 90(4), 651-657.
[http://dx.doi.org/10.1016/j.pbb.2008.05.008] [PMID: 18571706]
[29]
Balboni, G.; Salvadori, S.; Trapella, C.; Knapp, B.I.; Bidlack, J.M.; Lazarus, L.H.; Peng, X.; Neumeyer, J.L. Evolution of the bifunctional lead μ agonist/δ antagonist containing the dmt-tic opioid pharmacophore. ACS Chem. Neurosci., 2010, 1(2), 155-164.
[http://dx.doi.org/10.1021/cn900025j] [PMID: 20352071]
[30]
Dietis, N.; McDonald, J.; Molinari, S.; Calo, G.; Guerrini, R.; Rowbotham, D.J.; Lambert, D.G. Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505). Br. J. Anaesth., 2012, 108(2), 262-270.
[http://dx.doi.org/10.1093/bja/aer377] [PMID: 22194444]
[31]
Purington, L.C.; Sobczyk-Kojiro, K.; Pogozheva, I.D.; Traynor, J.R.; Mosberg, H.I. Development and in vitro characterization of a novel bifunctional μ-agonist/δ-antagonist opioid tetrapeptide. ACS Chem. Biol., 2011, 6(12), 1375-1381.
[http://dx.doi.org/10.1021/cb200263q] [PMID: 21958158]
[32]
Mosberg, H.I.; Yeomans, L.; Anand, J.P.; Porter, V.; Sobczyk-Kojiro, K.; Traynor, J.R.; Jutkiewicz, E.M. Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance. J. Med. Chem., 2014, 57(7), 3148-3153.
[http://dx.doi.org/10.1021/jm5002088] [PMID: 24641190]
[33]
Lowery, J.J.; Raymond, T.J.; Giuvelis, D.; Bidlack, J.M.; Polt, R.; Bilsky, E.J. In vivo characterization of MMP-2200, a mixed δ/μ opioid agonist, in mice. J. Pharmacol. Exp. Ther., 2011, 336(3), 767-778.
[http://dx.doi.org/10.1124/jpet.110.172866] [PMID: 21118955]
[34]
Vandormael, B.; Fourla, D.D.; Gramowski-Voss, A.; Kosson, P.; Weiss, D.G.; Schröder, O.H.; Lipkowski, A.; Georgoussi, Z.; Tourwé, D. Superpotent [Dmt1] dermorphin tetrapeptides containing the 4-aminotetrahydro-2-benzazepin-3-one scaffold with mixed μ/δ opioid receptor agonistic properties. J. Med. Chem., 2011, 54(22), 7848-7859.
[http://dx.doi.org/10.1021/jm200894e] [PMID: 21978284]
[35]
Sagan, S.; Karoyan, P.; Lequin, O.; Chassaing, G.; Lavielle, S. N- and Calpha-methylation in biologically active peptides: synthesis, structural and functional aspects. Curr. Med. Chem., 2004, 11(21), 2799-2822.
[http://dx.doi.org/10.2174/0929867043364108] [PMID: 15544477]
[36]
Kessler, H.; Chatterjee, J.; Doedens, L.; Opperer, F.; Gilon, C.; Hruby, V.J.; Mierke, D. New perspectives in peptide chemistry by Nalkylation. Biopolymers, 2007, 88, 519.
[37]
Healy, J.R.; Bezawada, P.; Shim, J.; Jones, J.W.; Kane, M.A.; MacKerell, A.D., Jr; Coop, A.; Matsumoto, R.R. Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities. ACS Chem. Neurosci., 2013, 4(9), 1256-1266.
[http://dx.doi.org/10.1021/cn4000428] [PMID: 23713721]
[38]
Brenner, D.M.; Sayuk, G.S. Current US Food and Drug Administration-Approved Pharmacologic Therapies for the Treatment of Irritable Bowel Syndrome with Diarrhea. Adv. Ther., 2020, 37(1), 83-96.
[PMID: 31707713]
[39]
Breslin, H.J.; Diamond, C.J.; Kavash, R.W.; Cai, C.; Dyatkin, A.B.; Miskowski, T.A.; Zhang, S.P.; Wade, P.R.; Hornby, P.J.; He, W. Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d). Bioorg. Med. Chem. Lett., 2012, 22(14), 4869-4872.
[http://dx.doi.org/10.1016/j.bmcl.2012.05.042] [PMID: 22695132]
[40]
Wade, P.R.; Palmer, J.M.; McKenney, S.; Kenigs, V.; Chevalier, K.; Moore, B.A.; Mabus, J.R.; Saunders, P.R.; Wallace, N.H.; Schneider, C.R.; Kimball, E.S.; Breslin, H.J.; He, W.; Hornby, P.J. Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist. Br. J. Pharmacol., 2012, 167(5), 1111-1125.
[http://dx.doi.org/10.1111/j.1476-5381.2012.02068.x] [PMID: 22671931]
[41]
Podolsky, A.T.; Sandweiss, A.; Hu, J.; Bilsky, E.J.; Cain, J.P.; Kumirov, V.K.; Lee, Y.S.; Hruby, V.J.; Vardanyan, R.S.; Vanderah, T.W. Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. Life Sci., 2013, 93(25-26), 1010-1016.
[http://dx.doi.org/10.1016/j.lfs.2013.09.016] [PMID: 24084045]
[42]
Li, J.; Wang, X.; Zhang, F.; Yin, H. Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases. Pharmacol. Ther., 2013, 138(3), 441-451.
[http://dx.doi.org/10.1016/j.pharmthera.2013.03.003] [PMID: 23531543]
[43]
Pasquinucci, L.; Prezzavento, O.; Marrazzo, A.; Amata, E.; Ronsisvalle, S.; Georgoussi, Z.; Fourla, D.D.; Scoto, G.M.; Parenti, C.; Aricò, G.; Ronsisvalle, G. Evaluation of N-substitution in 6,7-benzomorphan compounds. Bioorg. Med. Chem., 2010, 18(14), 4975-4982.
[http://dx.doi.org/10.1016/j.bmc.2010.06.005] [PMID: 20599386]
[44]
Parenti, C.; Turnaturi, R.; Aricò, G.; Marrazzo, A.; Prezzavento, O.; Ronsisvalle, S.; Scoto, G.M.; Ronsisvalle, G.; Pasquinucci, L. Antinociceptive profile of LP1, a non-peptide multitarget opioid ligand. Life Sci., 2012, 90(25-26), 957-961.
[http://dx.doi.org/10.1016/j.lfs.2012.04.041] [PMID: 22580287]
[45]
Pasquinucci, L.; Parenti, C.; Turnaturi, R.; Aricò, G.; Marrazzo, A.; Prezzavento, O.; Ronsisvalle, S.; Georgoussi, Z.; Fourla, D.D.; Scoto, G.M.; Ronsisvalle, G. The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment. Life Sci., 2012, 90(1-2), 66-70.
[http://dx.doi.org/10.1016/j.lfs.2011.10.024] [PMID: 22100511]
[46]
Lenard, N.R.; Daniels, D.J.; Portoghese, P.S.; Roerig, S.C. Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur. J. Pharmacol., 2007, 566(1-3), 75-82.
[http://dx.doi.org/10.1016/j.ejphar.2007.02.040] [PMID: 17383633]
[47]
Gomes, I.; Fujita, W.; Gupta, A.; Saldanha, S.A.; Negri, A.; Pinello, C.E.; Eberhart, C.; Roberts, E.; Filizola, M.; Hodder, P.; Devi, L.A. Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity. Proc. Natl. Acad. Sci. USA, 2013, 110(29), 12072-12077.
[http://dx.doi.org/10.1073/pnas.1222044110] [PMID: 23818586]
[48]
Derouiche, L.; Ugur, M.; Pierre, F.; Mann, A.; Doridot, S.; Ory, S.; Schulz, S.; Massotte, D. Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking., 2018 Available at:.https://www.biorxiv.org/content/10.1101/455147v1 (Accessed Oct 28, 2018).
[49]
Olson, K.M.; Keresztes, A.; Tashiro, J.K.; Daconta, L.V.; Hruby, V.J.; Streicher, J.M. Synthesis and evaluation of a novel bivalent selective antagonist for the mu-delta opioid receptor heterodimer that reduces morphine withdrawal in mice. J. Med. Chem., 2018, 61(14), 6075-6086.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00403] [PMID: 29939746]

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