Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins

References

• 1  Borsook D, Hargreaves RJ, Becerra L. Can functional magnetic resonance imaging improve success rates in central nervous system drug discovery? Expert Opin. Drug Disc.6,597–617 (2011).
  Medline CASGoogle Scholar
• 2  Banks WA. Delivery of peptides to the brain: emphasis on therapeutic development. Biopolymers90,589–594 (2008).
  Medline CASGoogle Scholar
• 3  Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Therap.104,29–45 (2004).
  Medline CASGoogle Scholar
• 4  Pardridge WM. Brain Drug Targeting. Cambridge University Press, Cambridge, UK (2001).
  Google Scholar
• 5  Gruber CW, Muttenthaler M, Freissmuth M. Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors. Curr. Pharm. Des.16(28),3071–3088 (2010).
  Medline CASGoogle Scholar
• 6  Ibáñez CF. Beyond the cell surface: new mechanisms of receptor function. Biochem. Biophys. Res. Commun.396(1),24–27 (2010).
  Medline CASGoogle Scholar
• 7  Cleland JL, Langer R. Formulation and Delivery of Proteins and Peptides. American Chemical Society, Washington, DC, USA (1994).
  Google Scholar
• 8  Taylor MD, Amidon GL. Peptide-Based Drug Design. American Chemical Society, Washington, DC, USA (1995).
  Google Scholar
• 9  Van der Walle C. Peptide and Protein Delivery. Academic Press, London, UK (2011).
  Google Scholar
• 10  Snyder SH. Opiate receptors and beyond: 30 years of neural signaling research. Neuropharmacology47,274–285 (2004).
  Medline CASGoogle Scholar
• 11  Lagerström MC, Schiöth HB. Structural diversity of G protein coupled receptors and significance for drug discovery. Nature Rev. Drug Disc.7,339–357 (2008).
  MedlineGoogle Scholar
• 12  Tyndall JDA, Pfeiffer B, Abbenante G, Fairlie DP. Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem. Rev.105,793–826 (2005).
  Medline CASGoogle Scholar
• 13  Martin WR, Eades CG, Thompson JA et al. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther.197,517–532 (1976).
  Medline CASGoogle Scholar
• 14  Evans CJ. Secrets of the opium poppy revealed. Neuropharmacology47,293–299 (2004).
  Medline CASGoogle Scholar
• 15  Chang K-J, Porreca F, Woods J. The Delta Receptor. Marcel Dekker, Inc., NY, USA (2004).
  Google Scholar
• 16  Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW. Endogenous opioid peptides: multiple agonists and receptors. Nature267,495–499 (1977).
  Medline CASGoogle Scholar
• 17  Yue X, Falk T, Zuniga LA et al. Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson’s disease. Brain Res.1413,72–83 (2011).
  Medline CASGoogle Scholar
• 18  Neumeyer JL, Zhang A, Xiong W et al. Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors. J. Med. Chem.46,5162–5170 (2003).
  Medline CASGoogle Scholar
• 19  Jordan BA, Devi L. G-protein-coupled receptor heterodimerization modulates receptor function. Nature399,697–700 (1999).
  Medline CASGoogle Scholar
• 20  Bhushan RG, Sharma SK, Xie Z et al. A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers. J. Med. Chem.47,2969–2972 (2004).
  Medline CASGoogle Scholar
• 21  Simantov R, Kuhar MJ, Uhl GR et al. Opioid peptide enkephalin: Immunohistochemical mapping in rat central nervous system. Proc. Natl Acad. Sci. USA74,2167–2171 (1977).
  Medline CASGoogle Scholar
• 22  Scherrer G, Imamachi N, Cao Y-Q et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell137,1148–1159 (2009).
  Medline CASGoogle Scholar
• 23  Schiller PW. Bi- or multifunctional opioid peptide drugs. Life Sci.86,598–603 (2010).
  Medline CASGoogle Scholar
• 24  Pradhan AA, Befort K, Nozaki C et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. TIPS32,581–590 (2011).
  Medline CASGoogle Scholar
• 25  Patkar KA, Murray TF, Aldrich JV. The effects of C-terminal modifications on the opioid activity of [N-benzyltyr1]dynorphin A-(1–11) analogues. J. Med. Chem.52,6814–6821 (2009).
  Medline CASGoogle Scholar
• 26  Binder W. Walker JS. Effect of the peripherally selective β-opioid agonist, asimadoline, on adjuvant arthritis. Br. J. Pharmacol.124,647–654 (1998).
  Medline CASGoogle Scholar
• 27  Stevenson GW, Folk JE, Linsenmayer DC et al. Opioid interactions in rhesus monkeys: effects of δ + µ and δ + κ agonists on schedule-controlled responding and thermal nociception. J. Pharm. Exp. Therap.307,1054–1064 (2003).
  Medline CASGoogle Scholar
• 28  Roth BL, Baner K, Westkaemper R et al. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc. Natl Acad. Sci. USA99,11934–11939 (2002).
  Medline CASGoogle Scholar
• 29  Aldrich JV, McLaughlin JP. Peptide kappa opioid receptor ligands: potential for drug development. AAPS J.11,312–322 (2009).
  Medline CASGoogle Scholar
• 30  Yamada H, Shimoyama N, Sora I et al. Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors. Brain Res.1083,61–69 (2006).
  Medline CASGoogle Scholar
• 31  Giardina G, Clarke GD, Grugni M et al. Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes. Farmaco50,405–418 (1995).
  Medline CASGoogle Scholar
• 32  Carroll I, Thomas JB, Dykstra LA et al. Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist. Eur. J. Pharmacol.501,111–9 (2004).
  Medline CASGoogle Scholar
• 33  Hökfelt T, Bartfai T, Bloom F. Neuropeptides: opportunities for drug discovery. Lancet Neurology2,463–472 (2003).
  MedlineGoogle Scholar
• 34  Cahill CM, Morinville A, Hoffert C et al. Up-regulation and trafficking of (opioid receptor in a model of chronic inflammation: implications for pain control. Pain101,199–208 (2003).
  Medline CASGoogle Scholar
• 35  Weber E, Escht FS, Bohlen P et al. Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain. Proc. Natl Acad. Sci. USA80,7362–7366 (1983).
  Medline CASGoogle Scholar
• 36  Arakawa K, De Jong W, Mulder AH et al. The electrically stimulated release of [3H]noradrenaline from nucleus tractus solitarii slices in vitro is modulated via β-opioid receptors. Eur. J. Pharm.192,311–316 (1991).
  Medline CASGoogle Scholar
• 37  Ronken E, Wiegant VM, Kaspersen FM et al. Topography and characteristics of specific binding sites for non-opioid β-type endorphins in the rat brain as studied by autoradiography with [35S]Met-desenkephalin-γ-endorphin. Brain Res.615,63–70 (1993).
  Medline CASGoogle Scholar
• 38  Navolotskaya E, Kovalitskaya YA, Zolotarev YA et al. Binding of synthetic fragments of β-endorphin to nonopioid β-endorphin receptor. J. Peptide Sci.14,1121–1128 (2008).
  Medline CASGoogle Scholar
• 39  Schwyzer R, Sargent DF. Membrane lipid phase as catalyst for peptide receptor interactions. Proc. Natl Acad. Sci. USA83,5774–78 (1986).
  MedlineGoogle Scholar
• 40  Tamm LK. Protein–Lipid Interactions. From Membrane Domains to Cellular Networks. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany (2005).
  Google Scholar
• 41  Adam G, Delbrück M. In: Structural Chemistry and Molecular Biology. Rich R, Davidson N (Eds). Freeman & Co., San Francisco, CA, USA, 198–199 (1968).
  Google Scholar
• 42  Saffman PG, Delbrück M. Brownian motion in biological membranes. Proc. Natl Acad. Sci. USA72,3111–3113 (1975).
  Medline CASGoogle Scholar
• 43  Segrest JP, Jackson RL, Morrisett JD et al. A molecular theory of lipid-protein interactions in the plasma lipoproteins. FEBS Lett.38,247–253 (1974).
  Medline CASGoogle Scholar
• 44  Epand RM, Shai Y, Segrest JP et al. Mechanisms for the modulation of membrane bilayer properties by amphipathic helical peptides. Biopolymers37,319–338 (1995).
  Medline CASGoogle Scholar
• 45  Pardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx: J. Am. Soc. Exp. NeuroTher.2,3–14 (2005).
  MedlineGoogle Scholar
• 46  Terasaki T, Hirai K, Sato H et al. Absorptive-mediated endocytosis of a dynorphin-like analgesic peptide, E-2078 into the blood–brain barrier. J. Pharm. Exp. Ther.251,351–357 (1989).
  Medline CASGoogle Scholar
• 47  Deguchi Y, Miyakawa Y, Sakurada S et al. Blood–brain barrier transport of a novel micro 1-specific opioid peptide, H-Tyr-D-Arg-Phe-beta-Ala-OH (TAPA). J. Neurochem.84,1154–1161 (2003).
  Medline CASGoogle Scholar
• 48  Kastin AJ, Pan W, Maness LM et al. Peptides crossing the blood–brain barrier: some unusual observations. Brain Res.848,96–100 (1999).
  Medline CASGoogle Scholar
• 49  Bredeloux P, Cavelier F, Dubuc I et al. Synthesis and biological effects of c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a new analogue of neurotensin that crosses the blood–brain barrier. J. Med. Chem.51,1610–1616 (2008).
  Medline CASGoogle Scholar
• 50  Egleton RD, Davis P. Development of neuropeptide drugs that cross the blood–brain barrier. NeuroRx: J. Am. Soc. Exp. NeuroTher.2,44–53 (2005).
  MedlineGoogle Scholar
• 51  Mehiri M, Chen W-H, Janout V et al. Molecular umbrella transport: exceptions to the classic size/lipophilicity rule. J. Am. Chem. Soc.131,1338–1339 (2009).
  Medline CASGoogle Scholar
• 52  Pardridge WM. Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses. Bioconjugate Chem.19,1327–1338 (2008).
  Medline CASGoogle Scholar
• 53  Malakoutikhah M, Teixidó M, Giralt E. Toward an optimal blood–brain barrier shuttle by synthesis and evaluation of peptide libraries. J. Med. Chem.51,4881–4889 (2008).
  Medline CASGoogle Scholar
• 54  Meldal M, Hilaire PM. Synthetic methods of glycopeptide assembly and biological analysis of glycopeptide products. Curr. Opin. Chem. Biol.1,552–563 (1997).
  Medline CASGoogle Scholar
• 55  Boons GJ, Polt R. The chemistry of O- and N-linked glycopeptides. In: Carbohydrate Chemistry. Blackie Press, London, UK, 223–242 (1998).
  Google Scholar
• 56  Eriko T, Yuko N, Yasuhiro K et al. Chemoenzymatic synthesis of a MUC1 glycopeptide carrying non-natural sialyl TF-beta O-glycan. Biosci. Biotech. Biochem.70,2515–2522 (2006).
  MedlineGoogle Scholar
• 57  Nianhuan Y, Gabriel F, Hamed M et al. Facile synthesis of glycosylated Fmoc amino acid building blocks assisted by microwave irradiation. Carbohydrate Res.345,2277–2281 (2010).
  MedlineGoogle Scholar
• 58  Polt R, Szabò LZ, Treiberg J et al. General methods for alpha-O-ser/thr or beta-O-ser/thr glycosides and glycopeptides. Solid-phase synthesis of O-glycosyl cyclic enkephalin analogues. J. Am. Chem. Soc.114,10249–58 (1992).
  CASGoogle Scholar
• 59  Mitchell SA, Pratt MR, Hruby VJ, Polt R. Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin. J. Org. Chem.66,2327–42 (2001).
  Medline CASGoogle Scholar
• 60  Keyari CM, Polt R. Serine and threonine Schiff base esters react with β-anomeric peracetates in the presence of BF₃•Et₂O to produce β-glycosides. J. Carbohydr. Chem.29,181–206 (2010).
  CASGoogle Scholar
• 61  Lefever MR, Szabò LZ, Anglin B et al. Glycosylation of β-amino acids by sugar acetate donors with InBr₃. Minimally competent Lewis acids. Carbohydr. Res.347, (2012) (In press).
  Google Scholar
• 62  Hruby VJ, Toth G, Gehring CA et al. Topographically designed analogues of [D-Pen2,D-Pen5]enkephalin. J. Med. Chem.34,1823–1830 (1991).
  Medline CASGoogle Scholar
• 63  Mosberg HI, Hurst R, Hruby VJ et al. Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors. Proc. Natl Acad. Sci. USA80,5871–5874 (1983).
  Medline CASGoogle Scholar
• 64  Weber SJ, Abbruscato TJ, Brownson EA et al. Assessment of an in vitro blood–brain barrier model using several [Met5]enkephalin opioid analogs. J. Pharm. Exp. Ther.266,1649–1655 (1993).
  Medline CASGoogle Scholar
• 65  Rodriguez RE, Rodriguez FD, Sacristan MP et al. New glycosylpeptides with high antinociceptive activity. Neurosci. Lett.101,89–94 (1989).
  Medline CASGoogle Scholar
• 66  Polt R, Porreca F, Szabò LZ et al. Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood–brain barrier. Proc. Natl Acad. Sci. USA91,7114–7118 (1994).
  Medline CASGoogle Scholar
• 67  Egleton RD, Mitchell SA, Huber JD et al. Improved bioavailability to the brain of glycosylated Met-enkephalin analogs. Brain Res.881,37–46 (2000).
  Medline CASGoogle Scholar
• 68  Zajac J-M, Gacel G, Petit F et al. Deltakephalin, Tyr-D-Thr-Gly-Phe-Leu-Thr : a new highly potent and fully specific agonist for opiate β-receptors. Biochem. Biophys. Res. Commun.111,390–397 (1983).
  Medline CASGoogle Scholar
• 69  Bilsky EJ, Egleton RD, Mitchell SA et al. Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J. Med. Chem.43,2586–2590 (2000).
  Medline CASGoogle Scholar
• 70  Egleton RD, Mitchell SA, Huber JD et al. Improved blood–brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J. Pharm. Exp. Therap.299,967–972 (2001).
  Medline CASGoogle Scholar
• 71  Horvat S. Opioid peptides and their glycoconjugates: structure-activity relationships. Curr. Med. Chem. – Central Nervous System Agents1,133–154 (2001).
  CASGoogle Scholar
• 72  Elmagbari NO, Egleton RD, Palian MM et al. Antinociceptive structure–activity studies with enkephalin-based opioid glycopeptides. J. Pharm. Exp. Therap.311,290–297 (2004).
  Medline CASGoogle Scholar
• 73  Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain64,493–501 (1996).
  Medline CASGoogle Scholar
• 74  Lowery JJ, Raymond TJ, Giuvelis D et al.In vivo characterization of MMP-2200, a mixed δ/µ opioid agonist, in mice. J. Pharmacol. Exp. Ther.336,767–78 (2011).
  Medline CASGoogle Scholar
• 75  Do Carmo GP, Polt R, Bilsky R et al. Behavioral pharmacology of the µ/ δ opioid glycopeptide MMP2200 in Rhesus monkeys. J. Pharm. Exp. Therap.326,939–948 (2008).
  Medline CASGoogle Scholar
• 76  Brainin-Mattos J, Smith ND, Malkmus S et al. Cancer-related bone pain is attenuated by a systemically available delta-opioid receptor agonist. Pain122,174–181 (2006).
  Medline CASGoogle Scholar
• 77  Codd EE, Carson JR, Colburn RW et al. JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence. J. Pharmacol. Exp. Ther..329,241–51 (2009).
  Medline CASGoogle Scholar
• 78  Otis V, Sarret P, Gendron L. Spinal activation of delta opioid receptors alleviates cancer-related bone pain. Neurosci.183,221–9 (2011).
  Medline CASGoogle Scholar
• 79  Bilsky EJ, Calderon SN, Wang T et al. SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist. J. Pharmacol. Exp. Ther.273,359–66 (1995).
  Medline CASGoogle Scholar
• 80  Bilsky EJ, Bernstein RN, Pasternak GW et al. Selective inhibition of [D-Ala2, Glu4]deltorphin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor. Life Sci.55,PL37–PL43 (1994).
  Medline CASGoogle Scholar
• 81  Wild KD, McCormick J, Bilsky EJ et al. Antinociceptive actions of BW373U86 in the mouse. J. Pharmacol. Exp. Ther.267,858–865 (1993).
  Medline CASGoogle Scholar
• 82  Kreil G, Barra D, Simmaco M et al. Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors. Eur. J. Pharmacol.162,123–128 (1989).
  Medline CASGoogle Scholar
• 83  Pradhan AA, Befort K, Nozaki C et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. TIPS32,581–90 (2011).
  Medline CASGoogle Scholar
• 84  Roemer D, Buescher HH, Hill RC et al. A synthetic enkephalin analogue with prolonged parenteral and oral analgesic activity. Nature268,547–549 (1977).
  Medline CASGoogle Scholar
• 85  Handa BK, Land AC, Lord JA et al. Analogues of β-LPH61-64 possesing selective agonist activity at β-opiate receptors. Eur. J. Pharmacol.70,531–540 (1981).
  Medline CASGoogle Scholar
• 86  Sargent DF, Schwyzer R. Membrane lipid phase as catalyst for peptide receptor interactions. Proc. Natl Acad. Sci. USA83,5774–5778 (1986).
  Medline CASGoogle Scholar
• 87  Lowery JJ, Yeomans L, Keyari CM et al. Glycosylation improves the central effects of DAMGO. Chem. Biol. Drug Des.69,41–47 (2007).
  Medline CASGoogle Scholar
• 88  Yeomans L, Muthu D, Lowery JJ et al. Phosphorylation of enkephalins: NMR and CD studies in aqueous and membrane-mimicking environments. Chem. Biol. Drug Des.78,749–56 (2011).
  Medline CASGoogle Scholar
• 89  Egleton RD, Bilsky EJ, Tollin G et al. Biousian glycopeptides penetrate the blood–brain barrier. Tetrahedron Asymm.16,65–75 (2005).
  CASGoogle Scholar
• 90  Taylor JW, Miller RJ, Kaiser ET. Structural characterization of beta-endorphin through the design, synthesis, and study of model peptides. Mol. Pharm.22,657–666 (1982).
  CASGoogle Scholar
• 91  Kaiser ET, Kézdy FJ. Amphiphilic secondary structure: design of peptide hormones. Science 223,249–255 (1984).
  Google Scholar
• 92  Palian MM, Boguslavsky VI, O’Brien DF et al. Glycopeptide-membrane interactions: glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media. J. Am. Chem. Soc.125(19),5823–5831 (2003).
  Medline CASGoogle Scholar
• 93  Dhanasekaran M, Alves I, Yeomans L et al. Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. J. Am. Chem. Soc.127,5435–5448 (2005).
  Medline CASGoogle Scholar
• 94  Neumann J, Couvineau A, Murail S et al. Class-B GPCR activation: is ligand helix-capping the key? TIBS33,314–319 (2008).
  Medline CASGoogle Scholar
• 95  Gronenborn AM, Bovermann G, Clore GM. A 1H-NMR study of the solution conformation of secretin. Resonance assignment and secondary structure. FEBS Lett.215,88–94 (1987).
  Medline CASGoogle Scholar
• 96  Neidigh JW, Fesinmeyer RM, Prickett KS et al. Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry40,13188–13200 (2001).
  Medline CASGoogle Scholar
• 97  Sasaki K, Dockerill S, Adamiak DA et al. X-ray analysis of glucagon and its relationship to receptor binding. Nature257,751–757 (1975).
  Medline CASGoogle Scholar
• 98  Jin L, Briggs Sl, Chandrasekhar S et al. Crystal structure of human parathyroid hormone 1–34 at 0.9-Å resolution. J. Biol. Chem.275,27238–27244 (2000).
  Medline CASGoogle Scholar
• 99  Inooka H, Ohtaki T, Kitahara O et al. Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat. Struct. Biol.8,161–165 (2001).
  Medline CASGoogle Scholar
• 100  Lefever MR. Design, synthesis and characterization of helical opioid glycopeptides and fluorescent derivatives including optimization of serine glycosylation utilizing sugar acetates. Ph.D. Dissertation, The University of Arizona, USA (2010).
  Google Scholar
• 101  Li Y. Design, synthesis, and characterization of helical opioid glycopeptide agonists: the study of the structure-activity relationship and transport of glycopeptides related to beta-endorphin and dynorphin. Ph.D. Dissertation, The University of Arizona, USA (2011).
  Google Scholar
• 102  Job GE, Kennedy RJ, Heitmann B et al. Temperature- and length-dependent energetics of formation for polyalanine helices in water: assignment of w(Ala)(n,T) and temperature-dependent CD ellipticity standards. J. Am. Chem. Soc.128,8227–8233 (2006).
  Medline CASGoogle Scholar
• 103  Chin DH, Woody RW, Rohl CA et al. Circular dichroism spectra of short, fixed-nucleus alanine helices. Proc. Natl Acad. Sci. USA99,15416–15421 (2002).
  Medline CASGoogle Scholar
• 104  Biondi B, Giannini E, Negri L et al. Opioid peptides: synthesis and biological activity of new endomorphin analogues. Int. J. Peptide Res. Therap.12,145–151 (2006).
  CASGoogle Scholar
• 105  Negri L, Lattanzi R, Tabacco F et al. Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration. J. Med. Chem.42,400–404 (1999).
  Medline CASGoogle Scholar
• 106  Biondi L, Filira F, Giannini E et al. Novel glycosylated [Lys7]-dermorphin analogues: synthesis, biological activity and conformational investigations. J. Pept. Sci.13,179–189 (2007).
  Medline CASGoogle Scholar
• 107  Dangoor D, Biondi B, Gobbo M et al. Novel glycosylated VIP analogs: synthesis, biological activity, and metabolic stability. J. Pept. Sci.14,321–328 (2008).
  Medline CASGoogle Scholar
• 201  Cox BM, Borsodi A, Caló G et al. Opioid receptors, introductory chapter. IUPHAR database. www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=50
  Google Scholar