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Current Topics in Medicinal Chemistry

Author(s): Hirokazu Mizoguchi* and Hideaki Fujii

DOI: 10.2174/1568026620666200922113430

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Exploring μ-Opioid Receptor Splice Variants as a Specific Molecular Target for New Analgesics

Page: [2866 - 2877] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Since a μ-opioid receptor gene containing multiple exons has been identified, the variety of splice variants for μ-opioid receptors have been reported in various species. Amidino-TAPA and IBNtxA have been discovered as new analgesics with different pharmacological profiles from morphine. These new analgesics show a very potent analgesic effect but do not have dependence liability. Interestingly, these analgesics show the selectivity to the morphine-insensitive μ-opioid receptor splice variants. The splice variants, sensitive to these new analgesics but insensitive to morphine, may be a better molecular target to develop the analgesics without side effects.

Keywords: μ-Opioid receptor, Splice variant, Narcotic analgesics, Amidino-TAPA, IBNtxA, Molecular target.

Graphical Abstract

[1]
Nishimura, S.L.; Recht, L.D.; Pasternak, G.W. Biochemical characterization of high-affinity 3H-opioid binding. Further evidence for Mu1 sites. Mol. Pharmacol., 1984, 25(1), 29-37.
[PMID: 6323950]
[2]
Pasternak, G.W.; Wood, P.J. Multiple mu opiate receptors. Life Sci., 1986, 38(21), 1889-1898.
[http://dx.doi.org/10.1016/0024-3205(86)90217-1] [PMID: 2872563]
[3]
Wolozin, B.L.; Pasternak, G.W. Classification of multiple morphine and enkephalin binding sites in the central nervous system. Proc. Natl. Acad. Sci. USA, 1981, 78(10), 6181-6185.
[http://dx.doi.org/10.1073/pnas.78.10.6181] [PMID: 6273857]
[4]
Pasternak, G.W. Pharmacological mechanisms of opioid analgesics. Clin. Neuropharmacol., 1993, 16(1), 1-18.
[http://dx.doi.org/10.1097/00002826-199302000-00001] [PMID: 8093680]
[5]
Elliott, J.; Smart, D.; Lambert, D.G.; Traynor, J.R. Characterisation of μ-opioid receptors on SH-SY5Y cells using naloxonazine and β-funaltrexamine. Eur. J. Pharmacol., 1994, 268(3), 447-450.
[http://dx.doi.org/10.1016/0922-4106(94)90072-8] [PMID: 7805771]
[6]
Sakurada, S.; Zadina, J.E.; Kastin, A.J.; Katsuyama, S.; Fujimura, T.; Murayama, K.; Yuki, M.; Ueda, H.; Sakurada, T. Differential involvement of μ-opioid receptor subtypes in endomorphin-1- and -2-induced antinociception. Eur. J. Pharmacol., 1999, 372(1), 25-30.
[http://dx.doi.org/10.1016/S0014-2999(99)00181-8] [PMID: 10374711]
[7]
Sato, T.; Sakurada, S.; Takahashi, N.; Sakurada, T.; Tan-No, K.; Wako, K.; Kisara, K. Contribution of spinal μ1-opioid receptors to morphine-induced antinociception. Eur. J. Pharmacol., 1999, 369(2), 183-187.
[http://dx.doi.org/10.1016/S0014-2999(99)00065-5] [PMID: 10206177]
[8]
Moskowitz, A.S.; Goodman, R.R. Autoradiographic analysis of mu1, mu2, and delta opioid binding in the central nervous system of C57BL/6BY and CXBK (opioid receptor-deficient) mice. Brain Res., 1985, 360(1-2), 108-116.
[http://dx.doi.org/10.1016/0006-8993(85)91226-0] [PMID: 3000528]
[9]
Moskowitz, A.S.; Goodman, R.R. Autoradiographic distribution of mu1 and mu2 opioid binding in the mouse central nervous system. Brain Res., 1985, 360(1-2), 117-129.
[http://dx.doi.org/10.1016/0006-8993(85)91227-2] [PMID: 3000529]
[10]
Moskowitz, A.S.; Terman, G.W.; Carter, K.R.; Morgan, M.J.; Liebeskind, J.C. Analgesic, locomotor and lethal effects of morphine in the mouse: strain comparisons. Brain Res., 1985, 361(1-2), 46-51.
[http://dx.doi.org/10.1016/0006-8993(85)91273-9] [PMID: 4084809]
[11]
Evans, C.J.; Keith, D.E., Jr; Morrison, H.; Magendzo, K.; Edwards, R.H. Cloning of a delta opioid receptor by functional expression. Science, 1992, 258(5090), 1952-1955.
[http://dx.doi.org/10.1126/science.1335167] [PMID: 1335167]
[12]
Kieffer, B.L.; Befort, K.; Gaveriaux-Ruff, C.; Hirth, C.G. The δ-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl. Acad. Sci. USA, 1992, 89(24), 12048-12052.
[http://dx.doi.org/10.1073/pnas.89.24.12048] [PMID: 1334555]
[13]
Chen, Y.; Mestek, A.; Liu, J.; Hurley, J.A.; Yu, L. Molecular cloning and functional expression of a μ-opioid receptor from rat brain. Mol. Pharmacol., 1993, 44(1), 8-12.
[PMID: 8393525]
[14]
Fukuda, K.; Kato, S.; Mori, K.; Nishi, M.; Takeshima, H. Primary structures and expression from cDNAs of rat opioid receptor δ- and μ-subtypes. FEBS Lett., 1993, 327(3), 311-314.
[http://dx.doi.org/10.1016/0014-5793(93)81011-N] [PMID: 8394245]
[15]
Wang, J.B.; Imai, Y.; Eppler, C.M.; Gregor, P.; Spivak, C.E.; Uhl, G.R. μ opiate receptor: cDNA cloning and expression. Proc. Natl. Acad. Sci. USA, 1993, 90(21), 10230-10234.
[http://dx.doi.org/10.1073/pnas.90.21.10230] [PMID: 8234282]
[16]
Bare, L.A.; Mansson, E.; Yang, D. Expression of two variants of the human μ opioid receptor mRNA in SK-N-SH cells and human brain. FEBS Lett., 1994, 354(2), 213-216.
[http://dx.doi.org/10.1016/0014-5793(94)01129-X] [PMID: 7957926]
[17]
Zimprich, A.; Simon, T.; Höllt, V. Cloning and expression of an isoform of the rat μ opioid receptor (rMOR1B) which differs in agonist induced desensitization from rMOR1. FEBS Lett., 1995, 359(2-3), 142-146.
[http://dx.doi.org/10.1016/0014-5793(95)00028-8] [PMID: 7532594]
[18]
Doyle, G.A.; Rebecca Sheng, X.; Lin, S.S.; Press, D.M.; Grice, D.E.; Buono, R.J.; Ferraro, T.N.; Berrettini, W.H. Identification of three mouse μ-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene, 2007, 388(1-2), 135-147.
[http://dx.doi.org/10.1016/j.gene.2006.10.017] [PMID: 17156941]
[19]
Doyle, G.A.; Sheng, X.R.; Lin, S.S.; Press, D.M.; Grice, D.E.; Buono, R.J.; Ferraro, T.N.; Berrettini, W.H. Identification of five mouse μ-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene, 2007, 395(1-2), 98-107.
[http://dx.doi.org/10.1016/j.gene.2007.02.004] [PMID: 17398041]
[20]
Kvam, T-M.; Baar, C.; Rakvåg, T.T.; Kaasa, S.; Krokan, H.E.; Skorpen, F. Genetic analysis of the murine μ opioid receptor: increased complexity of Oprm gene splicing. J. Mol. Med. (Berl.), 2004, 82(4), 250-255.
[http://dx.doi.org/10.1007/s00109-003-0514-z] [PMID: 14991152]
[21]
Pan, Y-X.; Xu, J.; Bolan, E.; Abbadie, C.; Chang, A.; Zuckerman, A.; Rossi, G.; Pasternak, G.W. Identification and characterization of three new alternatively spliced μ-opioid receptor isoforms. Mol. Pharmacol., 1999, 56(2), 396-403.
[http://dx.doi.org/10.1124/mol.56.2.396] [PMID: 10419560]
[22]
Pan, Y-X.; Xu, J.; Bolan, E.; Chang, A.; Mahurter, L.; Rossi, G.; Pasternak, G.W. Isolation and expression of a novel alternatively spliced mu opioid receptor isoform, MOR-1F. FEBS Lett., 2000, 466(2-3), 337-340.
[http://dx.doi.org/10.1016/S0014-5793(00)01095-4] [PMID: 10682855]
[23]
Pan, Y-X.; Xu, J.; Mahurter, L.; Bolan, E.; Xu, M.; Pasternak, G.W. Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene. Proc. Natl. Acad. Sci. USA, 2001, 98(24), 14084-14089.
[http://dx.doi.org/10.1073/pnas.241296098] [PMID: 11717463]
[24]
Pan, Y-X.; Xu, J.; Bolan, E.; Moskowitz, H.S.; Xu, M.; Pasternak, G.W. Identification of four novel exon 5 splice variants of the mouse μ-opioid receptor gene: functional consequences of C-terminal splicing. Mol. Pharmacol., 2005, 68(3), 866-875.
[http://dx.doi.org/10.1124/mol.105.011858] [PMID: 15939800]
[25]
Pasternak, G.W.; Pan, Y-X. Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev., 2013, 65(4), 1257-1317.
[http://dx.doi.org/10.1124/pr.112.007138] [PMID: 24076545]
[26]
Xu, J.; Xu, M.; Brown, T.; Rossi, G.C.; Hurd, Y.L.; Inturrisi, C.E.; Pasternak, G.W.; Pan, Y-X. Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action. J. Biol. Chem., 2013, 288(29), 21211-21227.
[http://dx.doi.org/10.1074/jbc.M113.458687] [PMID: 23760268]
[27]
Bolan, E.A.; Pan, Y-X.; Pasternak, G.W. Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm. Synapse, 2004, 51(1), 11-18.
[http://dx.doi.org/10.1002/syn.10277] [PMID: 14579421]
[28]
Pasternak, G.W. Multiple opiate receptors: déjà vu all over again. Neuropharmacology, 2004, 47(Suppl. 1), 312-323.
[http://dx.doi.org/10.1016/j.neuropharm.2004.07.004] [PMID: 15464147]
[29]
Hughes, J.; Smith, T.W.; Kosterlitz, H.W.; Fothergill, L.A.; Morgan, B.A.; Morris, H.R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature, 1975, 258(5536), 577-580.
[http://dx.doi.org/10.1038/258577a0] [PMID: 1207728]
[30]
Li, C.H.; Chung, D. Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc. Natl. Acad. Sci. USA, 1976, 73(4), 1145-1148.
[http://dx.doi.org/10.1073/pnas.73.4.1145] [PMID: 1063395]
[31]
Goldstein, A.; Tachibana, S.; Lowney, L.I.; Hunkapiller, M.; Hood, L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc. Natl. Acad. Sci. USA, 1979, 76(12), 6666-6670.
[http://dx.doi.org/10.1073/pnas.76.12.6666] [PMID: 230519]
[32]
Montecucchi, P.C.; de Castiglione, R.; Erspamer, V. Identification of dermorphin and Hyp6-dermorphin in skin extracts of the Brazilian frog Phyllomedusa rhodei. Int. J. Pept. Protein Res., 1981, 17(3), 316-321.
[http://dx.doi.org/10.1111/j.1399-3011.1981.tb01997.x] [PMID: 7287302]
[33]
Zadina, J.E.; Hackler, L.; Ge, L-J.; Kastin, A.J. A potent and selective endogenous agonist for the μ-opiate receptor. Nature, 1997, 386(6624), 499-502.
[http://dx.doi.org/10.1038/386499a0] [PMID: 9087409]
[34]
Mizoguchi, H.; Bagetta, G.; Sakurada, T.; Sakurada, S. Dermorphin tetrapeptide analogs as potent and long-lasting analgesics with pharmacological profiles distinct from morphine. Peptides, 2011, 32(2), 421-427.
[http://dx.doi.org/10.1016/j.peptides.2010.11.013] [PMID: 21126548]
[35]
Kisara, K.; Sakurada, S.; Sakurada, T.; Sasaki, Y.; Sato, T.; Suzuki, K.; Watanabe, H. Dermorphin analogues containing D-kyotorphin: structure-antinociceptive relationships in mice. Br. J. Pharmacol., 1986, 87(1), 183-189.
[http://dx.doi.org/10.1111/j.1476-5381.1986.tb10170.x] [PMID: 2869809]
[36]
Puglisi-Allegra, S.; Castellano, C.; Filibeck, U.; Oliverio, A.; Melchiorri, P. Behavioural data on dermorphins in mice. Eur. J. Pharmacol., 1982, 82(3-4), 223-227.
[http://dx.doi.org/10.1016/0014-2999(82)90518-0] [PMID: 7128688]
[37]
Negri, L.; Lattanzi, R.; Melchiorri, P. Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for μ-opioid receptors. Br. J. Pharmacol., 1995, 114(1), 57-66.
[http://dx.doi.org/10.1111/j.1476-5381.1995.tb14905.x] [PMID: 7712029]
[38]
Negri, L.; Improta, G. Distribution and metabolism of dermorphin in rats. Pharmacol. Res. Commun., 1984, 16(12), 1183-1191.
[http://dx.doi.org/10.1016/S0031-6989(84)80083-1] [PMID: 6522442]
[39]
Negri, L.; Erspamer, G.F.; Severini, C.; Potenza, R.L.; Melchiorri, P.; Erspamer, V. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two μ opioid receptor subtypes that modulate antinociception and catalepsy in the rat. Proc. Natl. Acad. Sci. USA, 1992, 89(15), 7203-7207.
[http://dx.doi.org/10.1073/pnas.89.15.7203] [PMID: 1353890]
[40]
Melchiorri, P.; Erspamer, G.F.; Erspamer, V.; Guglietta, A.; De Castiglione, R.; Faoro, F.; Perseo, G.; Piani, S.; Santangelo, F. Synthetic peptides related to the dermorphins. II. Synthesis and biological activities of new analogues. Peptides, 1982, 3(5), 745-748.
[http://dx.doi.org/10.1016/0196-9781(82)90009-2] [PMID: 7177920]
[41]
Melchiorri, P.; Negri, L. The dermorphin peptide family. Gen. Pharmacol., 1996, 27(7), 1099-1107.
[http://dx.doi.org/10.1016/0306-3623(95)02149-3] [PMID: 8981054]
[42]
Sasaki, Y.; Matsui, M.; Fujita, H.; Hosono, M.; Taguchi, M.; Suzuki, K.; Sakurada, S.; Sato, T.; Sakurada, T.; Kisara, K. The analgesic activity of D-Arg2-dermorphin and its N-terminal tetrapeptide analogs after subcutaneous administration in mice. Neuropeptides, 1985, 5(4-6), 391-394.
[http://dx.doi.org/10.1016/0143-4179(85)90036-8] [PMID: 2860597]
[43]
Broccardo, M.; Erspamer, V.; Falconieri Erspamer, G.; Improta, G.; Linari, G.; Melchiorri, P.; Montecucchi, P.C. Pharmacological data on dermorphins, a new class of potent opioid peptides from amphibian skin. Br. J. Pharmacol., 1981, 73(3), 625-631.
[http://dx.doi.org/10.1111/j.1476-5381.1981.tb16797.x] [PMID: 7195758]
[44]
Chaki, K.; Sakurada, S.; Sakurada, T.; Kisara, K.; Suzuki, K. N-terminal tetrapeptide of dermorphin and D-Arg-substituted tetrapeptides: inactivation process of the antinociceptive activity by peptidase. Life Sci., 1990, 46(23), 1671-1678.
[http://dx.doi.org/10.1016/0024-3205(90)90382-2] [PMID: 1972532]
[45]
Sasaki, Y.; Hosono, M.; Matsui, M.; Fujita, H.; Suzuki, K.; Sakurada, S.; Sakurada, T.; Kisara, K. On the degradation of dermorphin and D-Arg2-dermorphin analogs by a soluble rat brain extract. Biochem. Biophys. Res. Commun., 1985, 130(3), 964-970.
[http://dx.doi.org/10.1016/0006-291X(85)91709-7] [PMID: 2862871]
[46]
Sato, T.; Sakurada, S.; Sakurada, T.; Furuta, S.; Chaki, K.; Kisara, K.; Sasaki, Y.; Suzuki, K. Opioid activities of D-Arg2-substituted tetrapeptides. J. Pharmacol. Exp. Ther., 1987, 242(2), 654-659.
[PMID: 3612556]
[47]
Sasaki, Y.; Ambo, A.; Suzuki, K. Studies on analgesic oligopeptides. VII. Solid phase synthesis and biological properties of Tyr-D-Arg-Phe-β Ala-NH2 and its fluorinated aromatic amino acid derivatives. Chem. Pharm. Bull. (Tokyo), 1991, 39(9), 2316-2318.
[http://dx.doi.org/10.1248/cpb.39.2316] [PMID: 1804544]
[48]
Chaki, K.; Kawamura, S.; Kisara, K.; Sakurada, S.; Sakurada, T.; Sasaki, Y.; Sato, T.; Susuki, K. Antinociception and physical dependence produced by [D-Arg2] dermorphin tetrapeptide analogues and morphine in rats. Br. J. Pharmacol., 1988, 95(1), 15-22.
[http://dx.doi.org/10.1111/j.1476-5381.1988.tb16543.x] [PMID: 2905901]
[49]
Ogawa, T.; Miyamae, T.; Murayama, K.; Okuyama, K.; Okayama, T.; Hagiwara, M.; Sakurada, S.; Morikawa, T. Synthesis and structure-activity relationships of an orally available and long-acting analgesic peptide, Nα-amidino-Tyr-D-Arg-Phe-MeβAla-OH (ADAMB). J. Med. Chem., 2002, 45(23), 5081-5089.
[http://dx.doi.org/10.1021/jm010357t] [PMID: 12408719]
[50]
Sasaki, Y.; Matsui, M.; Taguchi, M.; Suzuki, K.; Sakurada, S.; Sato, T.; Sakurada, T.; Kisara, K. D-Arg2-dermorphin tetrapeptide analogs: a potent and long-lasting analgesic activity after subcutaneous administration. Biochem. Biophys. Res. Commun., 1984, 120(1), 214-218.
[http://dx.doi.org/10.1016/0006-291X(84)91435-9] [PMID: 6712689]
[51]
Schiller, P.W.; Nguyen, T.M.; Chung, N.N.; Lemieux, C. Dermorphin analogues carrying an increased positive net charge in their “message” domain display extremely high μ opioid receptor selectivity. J. Med. Chem., 1989, 32(3), 698-703.
[http://dx.doi.org/10.1021/jm00123a035] [PMID: 2537427]
[52]
Schiller, P.W.; Nguyen, T.M.; Berezowska, I.; Dupuis, S.; Weltrowska, G.; Chung, N.N.; Lemieux, C. Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur. J. Med. Chem., 2000, 35(10), 895-901.
[http://dx.doi.org/10.1016/S0223-5234(00)01171-5] [PMID: 11121615]
[53]
Marastoni, M.; Salvadori, S.; Balboni, G.; Borea, P.A.; Marzola, G.; Tomatis, R. Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues. J. Med. Chem., 1987, 30(9), 1538-1542.
[http://dx.doi.org/10.1021/jm00392a002] [PMID: 2887656]
[54]
Mizoguchi, H.; Watanabe, C.; Watanabe, H.; Moriyama, K.; Sato, B.; Ohwada, K.; Yonezawa, A.; Sakurada, T.; Sakurada, S. Involvement of endogenous opioid peptides in the antinociception induced by the novel dermorphin tetrapeptide analog amidino-TAPA. Eur. J. Pharmacol., 2007, 560(2-3), 150-159.
[http://dx.doi.org/10.1016/j.ejphar.2007.01.014] [PMID: 17307162]
[55]
Mizoguchi, H.; Kon-No, T.; Watanabe, H.; Watanabe, C.; Yonezawa, A.; Sato, T.; Sakurada, T.; Sakurada, S. Involvement of spinal release of α-neo-endorphin on the antinociceptive effect of TAPA. Peptides, 2013, 50, 139-144.
[http://dx.doi.org/10.1016/j.peptides.2013.10.003] [PMID: 24126280]
[56]
Mizoguchi, H.; Ito, K.; Watanabe, H.; Watanabe, C.; Katsuyama, S.; Fujimura, T.; Sakurada, T.; Sakurada, S. Contribution of spinal μ1-opioid receptors and dynorphin B to the antinociception induced by Tyr-D-Arg-Phe-Sar. Peptides, 2006, 27(11), 2786-2793.
[http://dx.doi.org/10.1016/j.peptides.2006.07.006] [PMID: 16919848]
[57]
Szeto, H.H.; Soong, Y.; Wu, D.; Qian, X.; Zhao, G.M. Endogenous opioid peptides contribute to antinociceptive potency of intrathecal [Dmt1]DALDA. J. Pharmacol. Exp. Ther., 2003, 305(2), 696-702.
[http://dx.doi.org/10.1124/jpet.102.048561] [PMID: 12606628]
[58]
Mizoguchi, H.; Watanabe, C.; Higashiya, T.; Takeda, S.; Moriyama, K.; Yonezawa, A.; Sato, T.; Komatsu, T.; Sakurada, T.; Sakurada, S. Involvement of mouse μ-opioid receptor splice variants in the spinal antinociception induced by the dermorphin tetrapeptide analog amidino-TAPA. Eur. J. Pharmacol., 2011, 651(1-3), 66-72.
[http://dx.doi.org/10.1016/j.ejphar.2010.10.049] [PMID: 21047509]
[59]
Mizoguchi, H.; Watanabe, C.; Higashiya, T.; Takeda, S.; Moriyama, K.; Aoki, Y.; Kon-no, T.; Takagi, H.; Yonezawa, A.; Sato, T.; Sakurada, T.; Sakurada, S. Distinct physiological role of amidino-TAPA-sensitive and DAMGO-insensitive μ-opioid receptor splice variants in the mouse spinal cord. Eur. J. Pharmacol., 2013, 711(1-3), 80-86.
[http://dx.doi.org/10.1016/j.ejphar.2013.04.014] [PMID: 23623932]
[60]
Spanagel, R.; Herz, A.; Shippenberg, T.S. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc. Natl. Acad. Sci. USA, 1992, 89(6), 2046-2050.
[http://dx.doi.org/10.1073/pnas.89.6.2046] [PMID: 1347943]
[61]
Mizoguchi, H.; Watanabe, C.; Osada, S.; Yoshioka, M.; Aoki, Y.; Natsui, S.; Yonezawa, A.; Kanno, S.; Ishikawa, M.; Sakurada, T.; Sakurada, S. Lack of a rewarding effect and a locomotor-enhancing effect of the selective μ-opioid receptor agonist amidino-TAPA. Psychopharmacology (Berl.), 2010, 212(2), 215-225.
[http://dx.doi.org/10.1007/s00213-010-1946-0] [PMID: 20683583]
[62]
Majumdar, S.; Burgman, M.; Haselton, N.; Grinnell, S.; Ocampo, J.; Pasternak, A.R.; Pasternak, G.W. Generation of novel radiolabeled opiates through site-selective iodination. Bioorg. Med. Chem. Lett., 2011, 21(13), 4001-4004.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.008] [PMID: 21621410]
[63]
Majumdar, S.; Grinnell, S.; Le Rouzic, V.; Burgman, M.; Polikar, L.; Ansonoff, M.; Pintar, J.; Pan, Y-X.; Pasternak, G.W. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc. Natl. Acad. Sci. USA, 2011, 108(49), 19778-19783.
[http://dx.doi.org/10.1073/pnas.1115231108] [PMID: 22106286]
[64]
Grinnell, S.G.; Majumdar, S.; Narayan, A.; Le Rouzic, V.; Ansonoff, M.; Pintar, J.E.; Pasternak, G.W. Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA. J. Pharmacol. Exp. Ther., 2014, 350(3), 710-718.
[http://dx.doi.org/10.1124/jpet.114.213199] [PMID: 24970924]
[65]
Wieskopf, J.S.; Pan, Y-X.; Marcovitz, J.; Tuttle, A.H.; Majumdar, S.; Pidakala, J.; Pasternak, G.W.; Mogil, J.S. Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene. Pain, 2014, 155(10), 2063-2070.
[http://dx.doi.org/10.1016/j.pain.2014.07.014] [PMID: 25093831]
[66]
Samoshkin, A.; Convertino, M.; Viet, C.T.; Wieskopf, J.S.; Kambur, O.; Marcovitz, J.; Patel, P.; Stone, L.S.; Kalso, E.; Mogil, J.S.; Schmidt, B.L.; Maixner, W.; Dokholyan, N.V.; Diatchenko, L. Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling. Sci. Rep., 2015, 5, 18198.
[http://dx.doi.org/10.1038/srep18198] [PMID: 26657998]
[67]
Pan, Y-X.; Xu, J.; Xu, M.; Rossi, G.C.; Matulonis, J.E.; Pasternak, G.W. Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc. Natl. Acad. Sci. USA, 2009, 106(12), 4917-4922.
[http://dx.doi.org/10.1073/pnas.0811586106] [PMID: 19273844]
[68]
Lu, Z.; Xu, J.; Rossi, G.C.; Majumdar, S.; Pasternak, G.W.; Pan, Y-X. Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J. Clin. Invest., 2015, 125(7), 2626-2630.
[http://dx.doi.org/10.1172/JCI81070] [PMID: 26011641]
[69]
Lu, Z.; Xu, J.; Xu, M.; Rossi, G.C.; Majumdar, S.; Pasternak, G.W.; Pan, Y-X. Truncated μ-opioid receptors with 6 transmembrane domains are essential for opioid analgesia. Anesth. Analg., 2018, 126(3), 1050-1057.
[http://dx.doi.org/10.1213/ANE.0000000000002538] [PMID: 28991118]
[70]
Schuller, A.G.P.; King, M.A.; Zhang, J.; Bolan, E.; Pan, Y-X.; Morgan, D.J.; Chang, A.; Czick, M.E.; Unterwald, E.M.; Pasternak, G.W.; Pintar, J.E. Retention of heroin and morphine-6 β-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat. Neurosci., 1999, 2(2), 151-156.
[http://dx.doi.org/10.1038/5706] [PMID: 10195199]
[71]
Sader, S.; Anant, K.; Wu, C. To probe interaction of morphine and IBNtxA with 7TM and 6TM variants of the human μ-opioid receptor using all-atom molecular dynamics simulations with an explicit membrane. Phys. Chem. Chem. Phys., 2018, 20(3), 1724-1741.
[http://dx.doi.org/10.1039/C7CP06745C] [PMID: 29265141]
[72]
Huang, W.; Manglik, A.; Venkatakrishnan, A.J.; Laeremans, T.; Feinberg, E.N.; Sanborn, A.L.; Kato, H.E.; Livingston, K.E.; Thorsen, T.S.; Kling, R.C.; Granier, S.; Gmeiner, P.; Husbands, S.M.; Traynor, J.R.; Weis, W.I.; Steyaert, J.; Dror, R.O.; Kobilka, B.K. Structural insights into µ-opioid receptor activation. Nature, 2015, 524(7565), 315-321.
[http://dx.doi.org/10.1038/nature14886] [PMID: 26245379]
[73]
Manglik, A.; Lin, H.; Aryal, D.K.; McCorvy, J.D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R.C.; Bernat, V.; Hübner, H.; Huang, X-P.; Sassano, M.F.; Giguère, P.M.; Löber, S. Da Duan; Scherrer, G.; Kobilka, B.K.; Gmeiner, P.; Roth, B.L.; Shoichet, B.K. Structure-based discovery of opioid analgesics with reduced side effects. Nature, 2016, 537(7619), 185-190.
[http://dx.doi.org/10.1038/nature19112] [PMID: 27533032]
[74]
Majumdar, S.; Subrath, J.; Le Rouzic, V.; Polikar, L.; Burgman, M.; Nagakura, K.; Ocampo, J.; Haselton, N.; Pasternak, A.R.; Grinnell, S.; Pan, Y-X.; Pasternak, G.W. Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants. J. Med. Chem., 2012, 55(14), 6352-6362.
[http://dx.doi.org/10.1021/jm300305c] [PMID: 22734622]
[75]
Politzer, P.; Lane, P.; Concha, M.C.; Ma, Y.; Murray, J.S. An overview of halogen bonding. J. Mol. Model., 2007, 13(2), 305-311.
[http://dx.doi.org/10.1007/s00894-006-0154-7] [PMID: 17013631]
[76]
Wilcken, R.; Zimmermann, M.O.; Lange, A.; Joerger, A.C.; Boeckler, F.M. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J. Med. Chem., 2013, 56(4), 1363-1388.
[http://dx.doi.org/10.1021/jm3012068] [PMID: 23145854]
[77]
Váradi, A.; Marrone, G.F.; Eans, S.O.; Ganno, M.L.; Subrath, J.J.; Le Rouzic, V.; Hunkele, A.; Pasternak, G.W.; McLaughlin, J.P.; Majumdar, S. Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior. ACS Chem. Neurosci., 2015, 6(11), 1813-1824.
[http://dx.doi.org/10.1021/acschemneuro.5b00153] [PMID: 26325040]
[78]
Grinnell, S.G.; Ansonoff, M.; Marrone, G.F.; Lu, Z.; Narayan, A.; Xu, J.; Rossi, G.; Majumdar, S.; Pan, Y-X.; Bassoni, D.L.; Pintar, J.; Pasternak, G.W. Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse, 2016, 70(10), 395-407.
[http://dx.doi.org/10.1002/syn.21914] [PMID: 27223691]
[79]
Marrone, G.F.; Lu, Z.; Rossi, G.; Narayan, A.; Hunkele, A.; Marx, S.; Xu, J.; Pintar, J.; Majumdar, S.; Pan, Y-X.; Pasternak, G.W. Tetrapeptide endomorphin analogs require both full length and truncated splice variants of the mu opioid receptor gene Oprm1 for analgesia. ACS Chem. Neurosci., 2016, 7(12), 1717-1727.
[http://dx.doi.org/10.1021/acschemneuro.6b00240] [PMID: 27648914]
[80]
Huang, P.; Kehner, G.B.; Cowan, A.; Liu-Chen, L-Y. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J. Pharmacol. Exp. Ther., 2001, 297(2), 688-695.
[PMID: 11303059]