Exploring pharmacological activities and signaling of morphinans substituted in position 6 as potent agonists interacting with the μ opioid receptor

Molecular Pain

Mariana Spetea²  Helmut Schmidhammer²  Andrew Coop⁵  John R Traynor¹  Louis S Harris⁴  Mario D Aceto⁴  Girolamo Calo³  Davide Malfacini³  Tanila Ben Haddou² 

[1] Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5632, USA;Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, Innsbruck A-6020, Austria;Department of Medical Sciences, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, Ferrara I-44121, Italy;Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0613, USA;Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD 21201, USA

关键词: Calcium mobilization;    G protein;    Signaling;    Analgesia;    Pain;    Oxycodone;    Morphine;    Agonist;    Opioid receptors;   

Others  :  1161783
DOI  :  10.1186/1744-8069-10-48

 received in 2014-03-05, accepted in 2014-07-17,  发布年份 2014

【 摘 要 】

Background

Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures.

Results

This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone.

Conclusion

Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.

【 授权许可】

   
2014 Ben Haddou et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Marchand S: Applied Pain Neurophysiology. In Pharmacology Of Pain. Edited by Beaulieu P, Lussier D, Porreca F, AH Dickenson AH. Seattle: International Association for the Study of Pain; 2010:3-26.
• [2]Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D: Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 2006, 10:287-333.
• [3]Marcus DA, Cope DK, Deodhar A, Payne R: Chronic Pain: An Atlas Of Investigation And Management. Oxford: Clinical Publishing; 2009.
• [4]Pasternak GW, Pan YX: Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 2013, 65:1257-1317.
• [5]Kieffer BL, Evans CJ: Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacol 2009, 56:205-212.
• [6]Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S: Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 2012, 485:321-326.
• [7]Spetea M, Asim MF, Wolber G, Schmidhammer H: The μ opioid receptor and ligands acting at the μ opioid receptor, as therapeutics and potential therapeutics. Curr Pharm Des 2013, 19:7415-7434.
• [8]Cox BM: Pharmacology Of Opioid Drugs. In The Opiate Receptors. Edited by Pasternak GW. New York: Humana Press; 2011:23-57.
• [9]Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L: Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 2008, 24:175-192.
• [10]Schmidhammer H, Spetea M: Synthesis of 14-alkoxymorphinan derivatives and their pharmacological actions. Top Curr Chem 2011, 299:63-91.
• [11]Spetea M, Schmidhammer H: Recent advances in the development of 14-alkoxy substituted morphinans as potent and safer opioid analgesics. Curr Med Chem 2012, 19:2442-2457.
• [12]Stavitskaya L, Coop A: Most recent developments and modifications of 14-alkylamino and 14-alkoxy-4,5-epoxymorphinan derivatives. Mini Rev Med Chem 2011, 11:1002-1008.
• [13]Lattanzi R, Spetea M, Schüllner F, Rief SB, Krassnig R, Negri L, Schmidhammer H: Synthesis and biological evaluation of 14-alkoxymorphinans. 22. Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities. J Med Chem 2005, 48:3372-3378.
• [14]Schmidhammer H, Aeppli L, Atwell L, Fritsch F, Jacobson AE, Nebuchla M, Sperk G: Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (-)-14-methoxy-N-methylmorphinan-6-ones. J Med Chem 1984, 27:1575-1579.
• [15]Pasternak GW, Hahn EF: Long-acting opiate agonists and antagonists: 14-Hydroxydihydromorphinone hydrazones. J Med Chem 1980, 23:674-676.
• [16]Varga E, Tóth G, Benyhe S, Hosztafi S, Borsodi A: Synthesis and binding of [3H]-oxymorphazone to rat brain membranes. Life Sci 1987, 40:1579-1588.
• [17]Krizsan D, Varga E, Hosztafi S, Benyhe S, Szücs M, Borsodi A: Irreversible blockade of the high and low affinity [3H]-naloxone binding sites by C-6 derivatives of morphinane-6-ones. Life Sci 1991, 48:439-451.
• [18]Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A: Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci 1999, 22:2011-2220.
• [19]Fürst Z, Borsodi A, Friedmann T, Hosztafi S: 6-Substituted oxycodone derivatives have strong antinociceptive effects and block irreversibly the low affinity [3H]-naloxone binding sites in rat brain. Pharm Res 1992, 25:31-32.
• [20]Fürst S, Hosztafi S, Friedmann T: Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists. Curr Med Chem 1995, 1:423-440.
• [21]Schütz J, Brandt W, Spetea M, Wurst K, Wunder G, Schmidhammer H: Synthesis of 6-amino acid substituted derivatives of the highly potent analgesic 14-O-methyloxymorphone. Helv Chim Acta 2003, 86:2142-2148.
• [22]Spetea M, Friedmann T, Riba P, Schütz J, Wunder G, Langer T, Schmidhammer H, Fürst S: In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone. Eur J Pharmacol 2004, 483:301-308.
• [23]Fürst S, Riba P, Friedmann T, Timar J, Al-Khrasani M, Obara I, Makuch W, Spetea M, Schütz J, Przewlocki R, Przewlocka B, Schmidhammer H: Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J Pharmacol Exp Ther 2005, 312:609-618.
• [24]Bileviciute-Ljungar I, Spetea M, Guo Y, Schütz J, Windisch P, Schmidhammer H: Peripherally mediated antinociception of the μ-opioid receptor agonist 2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation. J Pharmacol Exp Ther 2006, 317:220-227.
• [25]Obara I, Makuch W, Spetea M, Schütz J, Schmidhammer H, Przewlocki R, Przewlocka B: Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. Eur J Pharmacol 2007, 558:60-67.
• [26]Al-Khrasani M, Spetea M, Friedmann T, Riba P, Király K, Schmidhammer H, Furst S: DAMGO and 6β-glycine substituted 14-O-methyloxymorphone but not morphine show peripheral, preemptive antinociception after systemic administration in a mouse visceral pain model and high intrinsic efficacy in the isolated rat vas deferens. Brain Res Bull 2007, 74:369-375.
• [27]Spetea M, Windisch P, Guo Y, Bileviciute-Ljungar I, Schütz J, Asim MF, Berzetei-Gurske IP, Riba P, Király K, Fürst S, Al-Khrasani M, Schmidhammer H: Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies. J Med Chem 2011, 54:980-988.
• [28]Schmidhammer H, Spetea M, Windisch P, Schütz J, Riba P, Al-Khrasani M, Fürst S: Functionalization of the carbonyl group in position 6 of morphinan-6-ones. Development of novel 6-amino and 6-guanidino substituted 14-alkoxymorphinans. Curr Pharm Des 2013, 19:7391-7399.
• [29]Greiner E, Schottenberger H, Wurst K, Schmidhammer H: Novel class of morphinans with acrylonitrile incorporated substructures as key intermediates for non-oxygen-bridged opioid ligands. J Am Chem Soc 2001, 123:3840-3841.
• [30]Spetea M, Greiner E, Aceto MD, Harris LS, Coop A, Schmidhammer H: Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency. J Med Chem 2005, 48:5052-5055.
• [31]Schütz J, Windisch P, Kristeva E, Wurst K, Ongania KH, Horvath UE, Schottenberger H, Laus G, Schmidhammer H: Mechanistic diversity of the van Leusen reaction applied to 6-ketomorphinans and synthetic potential of the resulting acrylonitrile substructures. J Org Chem 2005, 70:5323-5326.
• [32]Le Bars D, Gozariu M, Cadden SW: Animal models of nociception. Pharmacol Rev 2001, 53:597-652.
• [33]Testa B, Mayer JM: Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology. Zürich: VHCA Verlag Helvetica Chimica Acta AG, and Weinheim: Wiley-VCR GmbH & Vo. KGaA; 2003.
• [34]Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC: Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore. J Med Chem 2010, 53:7902-7917.
• [35]Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE: Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at μ- and δ-opioid receptors. J Pharmacol Exp Ther 2004, 308:547-554.
• [36]Peckham EM, Traynor JR: Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague–Dawley rats. J Pharmacol Exp Ther 2006, 316:1195-1201.
• [37]Zhang Y, Wang Z, Cox DP, Civelli O: Study on the activation of the opioid receptors by a set of morphine derivatives in a well-defined assay system. Neurochem Res 2012, 37:410-416.
• [38]Zheng H, Chu J, Qiu Y, Loh HH, Law PY: Agonist-selective signaling is determined by the receptor location within the membrane domains. Proc Natl Acad Sci U S A 2008, 105:9421-9426.
• [39]Ge X, Qiu Y, Loh HH, Law PY: GRIN1 regulates micro-opioid receptor activities by tethering the receptor and G protein in the lipid raft. J Biol Chem 2009, 284:36521-36534.
• [40]Raehal KM, Schmid CL, Groer CE, Bohn LM: Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol Rev 2011, 63:1001-1019.
• [41]Levitt ES, Clark MJ, Jenkins PM, Martens JR, Traynor JR: Differential effect of membrane cholesterol removal on μ- and δ-opioid receptors: a parallel comparison of acute and chronic signaling to adenylyl cyclase. J Biol Chem 2009, 284:22108-22122.
• [42]Pradhan AA, Smith ML, Kieffer BL, Evans CL: Ligand-directed signaling within the opioid receptor family. Br J Pharmacol 2012, 167:960-969.
• [43]Kelly E: Efficacy and ligand bias at the μ-opioid receptor. Br J Pharmacol 2013, 169:1430-1446.
• [44]Raehal KM, Bohn LM: β-Arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia. Handb Exp Pharmacol 2014, 219:427-443.
• [45]Kobylecki RJ, Carling RW, Lord JA, Smith CF, Lane AC: Common anionic receptor site hypothesis: its relevance to the antagonist action of naloxone. J Med Chem 1982, 25:116-120.
• [46]Bradford MM: A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248-254.
• [47]Lee KO, Akil H, Woods JH, Traynor JR: Differential binding properties of oripavines at cloned μ- and δ-opioid receptors. Eur J Pharmacol 1999, 378:323-330.
• [48]Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY: Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands. J Pharmacol Exp Ther 1997, 282:676-684.
• [49]Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O’Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS: Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 1998, 178:440-466.
• [50]Camarda V, Calo G: Chimeric G proteins in fluorimetric calcium assays: experience with opioid receptors. Methods Mol Biol 2013, 937:293-306.
• [51]Schütz J, Spetea M, Koch M, Aceto MD, Harris LS: Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-Phenylpropoxymetopon: an extremely powerful analgesic. J Med Chem 2003, 46:4182-4187.
• [52]Eddy NB, Leimbach D: Synthetic analgesics. II. Dithienylbutenyl-and dithienylbutylamines. J Pharmacol Exp Ther 1953, 107:385-393.
• [53]D’Amour FE, Smith DL: A method for determining loss of pain sensation. J Pharmacol Exp Ther 1941, 72:74-79.
• [54]Aceto MD, Harris LS, Bowman ER: Etorphines: μ-opioid receptor-selective antinociception and low physical dependence capacity. Eur J Pharmacol 1997, 338:215-223.
• [55]Litchfield JT Jr, Wilcoxon F: A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 1949, 96:99-113.