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Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development

  • Review Article
  • Theme: NIDA Symposium: Drugs of Abuse: Special Topics in Drug Development
  • Published:
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Abstract

While narcotic analgesics such as morphine, which act preferentially through mu opioid receptors, remain the gold standard in the treatment of severe pain, their use is limited by detrimental liabilities such as respiratory depression and drug dependence. Thus, there has been considerable interest in developing ligands for kappa opioid receptors (KOR) as potential analgesics and for the treatment of a variety of other disorders. These include effects mediated both by central receptors, such as antidepressant activity and a reduction in cocaine-seeking behavior, and activity resulting from the activation of peripheral receptors, such as analgesic and anti-inflammatory effects. While the vast majority of opioid receptor ligands that have progressed in preclinical development have been small molecules, significant advances have been made in recent years in identifying opioid peptide analogs that exhibit promising in vivo activity. This review will focus on possible therapeutic applications of ligands for KOR and specifically on the potential development of peptide ligands for these receptors.

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Abbreviations

BBB:

blood–brain barrier

BBMEC:

bovine brain microvessel endothelial cell

CPP:

conditioned place preference

DOR:

delta opioid receptor

Dyn:

dynorphin

GNTI:

5’-guanidinonaltrindole

i.c.v.:

intracerebroventricular

i.t.:

intrathecal

KOR:

kappa opioid receptor

MOR:

mu opioid receptor

norBNI:

nor-binaltorphimine

s.c.:

subcutaneous

SIA:

stress-induced analgesia

References

  1. Gutstein HB, Akil H. Opioid analgesics. In: Hardman J, Limbird L, Gilman A, editors. Goodman and Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; 2001. p. 569–619.

    Google Scholar 

  2. Aldrich JV, Vigil-Cruz SC. Narcotic analgesics. In: Abraham DJ, editor. Burger's medicinal chemistry & drug discovery. vol 6. Hoboken: Wiley; 2003. p. 329–481.

    Google Scholar 

  3. Coop A, Rice KC. Role of δ-opioid receptors in biological processes. Drug News Perspect 2000;13:481–7.

    PubMed  CAS  Google Scholar 

  4. Prisinzano TE, Tidgewell K, Harding WW. Kappa opioids as potential treatments for stimulant dependence. AAPS J 2005;7:E592–9.

    PubMed  CAS  Google Scholar 

  5. Metcalf MD, Coop A. Kappa opioid antagonists: past successes and future prospects. AAPS J 2005;7:E704–22.

    PubMed  CAS  Google Scholar 

  6. Schiller PW. Opioid peptide-derived analgesics. AAPS J 2005;7:E560–5.

    PubMed  CAS  Google Scholar 

  7. Polt R, Dhanasekaran M, Keyari CM. Glycosylated neuropeptides: a new vista for neuropsychopharmacology? Med Res Rev 2005;25:557–85.

    PubMed  CAS  Google Scholar 

  8. Knapp RJ, Malatynska E, Collins N, Fang L, Wang JY, Hruby VJ, Roeske WR, Yamamura HI. Molecular biology and pharmacology of cloned opioid receptors. FASEB J 1995;9:516–25.

    PubMed  CAS  Google Scholar 

  9. Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000;40:389–430.

    PubMed  CAS  Google Scholar 

  10. Fukuda K, Kato S, Morikawa H, Shoda T, Mori K. Functional coupling of the delta-, mu-, and kappa-opioid receptors to mitogen-activated protein kinase and arachidonate release in Chinese hamster ovary cells. J Neurochem 1996;67:1309–16.

    PubMed  CAS  Google Scholar 

  11. Aldrich JV. Opioid peptides. In: Howl J, Jones S, editors. Bioactive peptides. Boca Raton: CRC; 2009. p. 103–36.

    Google Scholar 

  12. Inan S, Cowan A. Kappa opioid agonists suppress chloroquine-induced scratching in mice. Eur J Pharmacol 2004;502:233–7.

    PubMed  CAS  Google Scholar 

  13. Barber A, Gottschlich R. Novel developments with selective, non-peptidic kappa-opioid receptor agonists. Exp Opin Investig Drugs 1997;6:1351–68.

    CAS  Google Scholar 

  14. DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des 2004;10:743–57.

    PubMed  CAS  Google Scholar 

  15. Bodnar RJ. Endogenous opiates and behavior: 2007. Peptides 2008;29:2292–375.

    PubMed  CAS  Google Scholar 

  16. Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A 1992;89:2046–50.

    PubMed  CAS  Google Scholar 

  17. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990;250:1429–32.

    PubMed  CAS  Google Scholar 

  18. Kalivas PW. Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Brain Res Rev 1993;18:75–113.

    PubMed  CAS  Google Scholar 

  19. Shippenberg TS, Zapata A, Chefer VI. Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 2007;116:306–21.

    PubMed  CAS  Google Scholar 

  20. Chefer VI, Czyzyk T, Bolan EA, Moron J, Pinta JE, Shippenberg TS. Endogenous κ-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. J Neurosci 2005;25:5029–37.

    PubMed  CAS  Google Scholar 

  21. Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Effect of the endogenous kappa opioid agonist dynorphin A(1-17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice. Psychopharmacology (Berl) 2004;172:422–9.

    CAS  Google Scholar 

  22. Takahashi M, Senda T, Tokuyama S, Kaneto H. Further evidence for the implication of a kappa-opioid receptor mechanism in the production of psychological stress-induced analgesia. Jpn J Pharmacol 1990;53:487–94.

    PubMed  CAS  Google Scholar 

  23. McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 2003;23:5674–83.

    PubMed  CAS  Google Scholar 

  24. McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C. Prior activation of kappa opioid receptors by U50,488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 2006;31:787–94.

    PubMed  CAS  Google Scholar 

  25. Starec M, Rosina J, Malek J, Krsiak M. Influence of dynorphin A (1-13) and dynorphin A (1-10) amide on stress-induced analgesia. Physiol Res 1996;45:433–8.

    PubMed  CAS  Google Scholar 

  26. Katoh A, Nabeshima T, Kameyama T. Behavioral changes induced by stressful situations—effects of enkephalins, dynorphin, and their interactions. J Pharmacol Exp Ther 1990;253:600–7.

    PubMed  CAS  Google Scholar 

  27. Nabeshima T, Katoh A, Wada M, Kameyama T. Stress-induced changes in brain Met-enkephalin, Leu-enkephalin and dynorphin concentrations. Life Sci 1992;51:211–7.

    PubMed  CAS  Google Scholar 

  28. Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS. Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. J Neurochem 2004;90:1258–68.

    PubMed  CAS  Google Scholar 

  29. Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci 2001;21:7397–403.

    PubMed  CAS  Google Scholar 

  30. Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WCJ, Jones RM, Portoghese PS, Carlezon WA Jr. Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther 2003;305:323–30.

    PubMed  CAS  Google Scholar 

  31. Shaham Y, Stewart J. Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats. Psychopharmacology (Berl) 1994;114:523–7.

    CAS  Google Scholar 

  32. Piazza PV, Le Moal ML. Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu Rev Pharmacol Toxicol 1996;36:359–78.

    PubMed  CAS  Google Scholar 

  33. American Psychiatric Association. Anxiety disorders. In: Francis A, Pincus HA, First MB, editors. Diagnostic and statistical manual of mental disorders. Philadelphia: American Psychiatric Association; 2000. p. 429–72.

  34. Millan MJ. Kappa-opioid receptors and analgesia. Trends Pharmacol Sci 1990;11:70–6.

    PubMed  CAS  Google Scholar 

  35. Walker JS. Anti-inflammatory effects of opioids. Adv Exp Med Biol 2003;521:148–60.

    PubMed  CAS  Google Scholar 

  36. Ko MC, Butelman ER, Woods JH. Activation of peripheral κ opioid receptors inhibits capsaicin-induced thermal nociception in rhesus monkeys. J Pharmacol Exp Ther 1999;289:378–85.

    PubMed  CAS  Google Scholar 

  37. Bileviciute-Ljungar I, Saxne T, Spetea M. Anti-inflammatory effects of contralateral administration of the kappa-opioid agonist U-50,488H in rats with unilaterally induced adjuvant arthritis. Rheumatology (Oxford) 2006;45:295–302.

    CAS  Google Scholar 

  38. Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004;141:1331–4.

    PubMed  CAS  Google Scholar 

  39. Gebhart GF, Su X, Joshi S, Ozaki N, Sengupta JN. Peripheral opioid modulation of visceral pain. Ann N Y Acad Sci 2000;909:41–50.

    PubMed  CAS  Google Scholar 

  40. Tortella FC, Decoster MA. Kappa opioids: therapeutic considerations in epilepsy and CNS injury. Clin Neuropharmacol 1994;17:403–16.

    PubMed  CAS  Google Scholar 

  41. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62:111–23.

    PubMed  CAS  Google Scholar 

  42. Peterson PK, Gekker G, Lokensgard JR, Bidlack JM, Chang AC, Fang X, Portoghese PS. Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes. Biochem Pharmacol 2001;61:1145–51.

    PubMed  CAS  Google Scholar 

  43. Pan ZZ. μ-Opposing actions of the κ-opioid receptors. Trends Pharmacol Sci 1998;19:94–8.

    PubMed  CAS  Google Scholar 

  44. Greenwald MK, Stitzer ML, Haberny KA. Human pharmacology of the opioid neuropeptide dynorphin A(1-13). J Pharmacol Exp Ther 1997;281:1154–63.

    PubMed  CAS  Google Scholar 

  45. Specker S, Wananukul W, Hatsukami D, Nolin K, Hooke L, Kreek MJ, Pentel PR. Effects of dynorphin A(1-13) on opiate withdrawal in humans. Psychopharmacology (Berl) 1998;137:326–32.

    CAS  Google Scholar 

  46. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by κ opiate receptors. Science 1986;233:774–6.

    PubMed  CAS  Google Scholar 

  47. Mello N, Negus SS. Interactions between kappa opioid agonists and cocaine. Preclinical studies. Ann N Y Acad Sci 2000;909:104–32.

    Article  PubMed  CAS  Google Scholar 

  48. Cohen BM, Murphy B. The effects of pentazocine, a kappa agonist, in patients with mania. Int J Neuropsychopharmacol 2008;11:243–7.

    PubMed  CAS  Google Scholar 

  49. Negus SS, Mello NK. Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys. Exp Clin Psychopharmacol 1999;7:307–17.

    PubMed  CAS  Google Scholar 

  50. Mori T, Nomura M, Nagase H, Narita M, Suzuki T. Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacology (Berl) 2002;161:17–22.

    CAS  Google Scholar 

  51. Fuentealba JA, Gysling K, Magendzo K, Andres ME. Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens. J Neurosci Res 2006;84:450–9.

    PubMed  CAS  Google Scholar 

  52. Heidbreder CA, Schenk S, Partridge B, Shippenberg TS. Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist. Synapse 1998;30:255–62.

    PubMed  CAS  Google Scholar 

  53. Thompson AC, Zapata A, Justice JB Jr, Vaughan RA, Sharpe LG, Shippenberg TS. Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci 2000;20:9333–40.

    PubMed  CAS  Google Scholar 

  54. Negus SS. Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berl) 2004;176:204–13.

    Google Scholar 

  55. Reindl JD, Rowan K, Carey AN, Peng X, Neumeyer JL, McLaughlin JP. Antidepressant-like effects of the novel kappa opioid antagonist MCL-144B in the forced-swim test. Pharmacology 2008;81:229–35.

    PubMed  CAS  Google Scholar 

  56. Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr. Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 2007;323:838–45.

    PubMed  CAS  Google Scholar 

  57. Beardsley PM, Howard JL, Shelton KL, Carroll FI. Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl) 2005;183:118–26.

    CAS  Google Scholar 

  58. Carey AN, Borozny K, Aldrich JV, McLaughlin JP. Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 2007;569:84–9.

    PubMed  CAS  Google Scholar 

  59. Rothman RB, Gorelick DA, Heishman SJ, Eichmiller PR, Hill BH, Norbeck J, Liberto JG. An open-label study of a functional opioid κ antagonist in the treatment of opioid dependence. J Substance Abuse Treat 2000;18:277–81.

    CAS  Google Scholar 

  60. Delvaux M. Pharmacology and clinical experience with fedotozine. Exp Opin Investig Drugs 2001;10:97–110.

    CAS  Google Scholar 

  61. Callahan MJ. Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. J Clin Gastroenterol 2002;35:S58–67.

    PubMed  CAS  Google Scholar 

  62. Jonker JW, Wagenaar E, van Deemter L, Gottschlich R, Bender HM, Dasenbrock J, Schinkel AH. Role of blood–brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgesic drug. Br J Pharmacol 1999;127:43–50.

    PubMed  CAS  Google Scholar 

  63. Camilleri M. Novel pharmacology: asimadoline, a kappa-opioid agonist, and visceral sensation. Neurogastroenterol Motil 2008;20:971–9.

    PubMed  CAS  Google Scholar 

  64. Machelska H, Pfluger M, Weber W, Piranvisseh-Volk M, Daubert JD, Dehaven R, Stein C. Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J Pharmacol Exp Ther 1999;290:354–61.

    PubMed  CAS  Google Scholar 

  65. Eisenach JC, Carpenter R, Curry R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain 2003;101:89–95.

    PubMed  CAS  Google Scholar 

  66. Vanderah TW, Schteingart CD, Trojnar J, Junien JL, Lai J, Riviere PJ. FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): a peripheral efficacious kappa opioid agonist with unprecedented selectivity. J Pharmacol Exp Ther 2004;310:326–33.

    PubMed  CAS  Google Scholar 

  67. Binder W, Machelska H, Mousa S, Schmitt T, Rivière PJM, Junien J-L, Stein C, Schäfer MJ. Analgesic and antiinflammatory effects of two novel κ-opioid peptides. Anesthesiology 2001;94:1034–44.

    PubMed  CAS  Google Scholar 

  68. Vanderah TW, Largent-Milnes T, Lai J, Porreca F, Houghten RA, Menzaghi F, Wisniewski K, Stalewski J, Sueiras-Diaz J, Galyean R, Schteingart C, Junien JL, Trojnar J, Riviere PJ. Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors. Eur J Pharmacol 2008;583:62–72.

    PubMed  CAS  Google Scholar 

  69. Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB. Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist. Proc Natl Acad Sci U S A 2002;99:11934–9.

    PubMed  CAS  Google Scholar 

  70. Butelman ER, Harris TJ, Kreek MJ. The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology (Berl) 2004;172:220–4.

    CAS  Google Scholar 

  71. Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ. Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans. J Pharmacol Exp Ther 2007;320:300–6.

    PubMed  CAS  Google Scholar 

  72. Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Mutational evidence for a common κ antagonist binding pocket in the wild-type κ and mutant μ[K303E] opioid receptors. J Med Chem 1998;41:4911–4.

    PubMed  CAS  Google Scholar 

  73. Thomas JB, Atkinson RN, Rothman RB, Fix SE, Mascarella SW, Vinson NA, Xu H, Dersch CM, Lu Y, Cantrell BE, Zimmerman DM, Carroll FI. Identification of the first trans-(3R,4R-dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity. J Med Chem 2001;44:2687–90.

    PubMed  CAS  Google Scholar 

  74. Goldstein A, Fischli W, Lowney LI, Hunkapiller M, Hood L. Porcine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide. Proc Natl Acad Sci U S A 1981;78:7219–23.

    PubMed  CAS  Google Scholar 

  75. Butelman ER, France CP, Woods JH. Agonist and antagonist effects of dynorphin A-(1-13) in a thermal antinociception assay in rhesus monkeys. J Pharmacol Exp Ther 1995;275:374–80.

    PubMed  CAS  Google Scholar 

  76. Butelman ER, Harris TJ, Perez A, Kreek MJ. Effects of systematically administered dynorphin A(1-17) in rhesus monkeys. J Pharmacol Exp Ther 1999;290:678–86.

    PubMed  CAS  Google Scholar 

  77. Butelman ER, Ball JW, Kreek MJ. Peripheral selectivity and apparent efficacy of dynorphins: comparison to non-peptidic kappa-opioid agonists in rhesus monkeys. Psychoneuroendocrinology 2004;29:307–26.

    PubMed  CAS  Google Scholar 

  78. Wen HL, Mehal ZD, Ong BH, Ho WK. Treatment of pain in cancer patients by intrathecal administration of dynorphin. Peptides 1987;8:191–3.

    PubMed  CAS  Google Scholar 

  79. Gambus PL, Schnider TW, Minto CF, Youngs EJ, Billard V, Brose WG, Hochhaus G, Shafer SL. Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers. Clin Pharmacol Ther 1998;64:27–38.

    PubMed  CAS  Google Scholar 

  80. Kreek MJ, Schluger J, Borg L, Gundoz M, Ho A. Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther 1999;288:260–9.

    PubMed  CAS  Google Scholar 

  81. King AC, Ho A, Schluger J, Borg L, Kreek MJ. Acute subjective effects of dynorphin A(1-13) infusion in normal healthy subjects. Drug Alcohol Dependence 1999;54:87–90.

    CAS  Google Scholar 

  82. Smith AP, Lee NM. Pharmacology of dynorphins. Annu Rev Pharmacol Toxicol 1988;28:123–40.

    PubMed  CAS  Google Scholar 

  83. Baskin DS, Widmayer MA, Browning JL, Heizer ML, Schmidt WK. Evaluation of delayed treatment of focal cerebral ischemia with three selective κ-opioid agonists in cats. Stroke 1994;25:2047–53.

    PubMed  CAS  Google Scholar 

  84. Leslie FM, Goldstein A. Degradation of dynorphin-(1-13) by membrane-bound rat brain enzymes. Neuropeptides 1982;2:185–96.

    CAS  Google Scholar 

  85. Seyfried CA, Tobler P. High-performance liquid chromatographic system for the separation of dynorphin-A (1-17) fragments and its application in enzymolysis studies with rat nerve terminal membranes. J Chromatogr B Biomed Appl 1990;529:43–54.

    CAS  Google Scholar 

  86. Yu J, Butelman ER, Woods JH, Chait BT, Kreek MJ. In vitro biotransformation of dynorphin A-(1-17) is similar in human and rhesus monkey blood as studied by matrix-assisted laser desorption/ionization mass spectrometry. J Pharmacol Exp Ther 1996;279:507–14.

    PubMed  CAS  Google Scholar 

  87. Chou JZ, Chait BT, Wang R, Kreek MJ. Differential biotransformation of dynorphin A(1-17) and dynorphin A(1-13) peptides in human blood, ex vivo. Peptides 1996;17:983–90.

    PubMed  CAS  Google Scholar 

  88. Reed B, Zhang Y, Chait BT, Kreek MJ. Dynorphin A(1-17) biotransformation in striatum of freely moving rats using microdialysis and matrix-assisted laser desorption/ionization mass spectrometry. J Neurochem 2003;86:815–23.

    PubMed  CAS  Google Scholar 

  89. Klintenberg R, Andren PE. Altered extracellular striatal in vivo biotransformation of the opioid neuropeptide dynorphin A(1-17) in the unilateral 6-OHDA rat model of Parkinson's disease. J Mass Spectrom 2005;40:261–70.

    PubMed  CAS  Google Scholar 

  90. Brugos B, Hochhaus G. Metabolism of dynorphin A(1-13). Pharmazie 2004;59:339–43.

    PubMed  CAS  Google Scholar 

  91. Prokai L, Kim H-S, Zharikova A, Roboz J, Ma L, Deng L, Simonsick WJ. Electrospray ionization mass spectrometric and liquid chromatographic–mass spectrometric studies on the metabolism of synthetic dynorphin A peptides in brain tissue in vitro and in vivo. J Chromatogr A 1998;800:59–68.

    PubMed  CAS  Google Scholar 

  92. Chavkin C, Goldstein A. A specific receptor for the opioid peptide dynorphin: structure–activity relationships. Proc Natl Acad Sci U S A 1981;78:6543–7.

    PubMed  CAS  Google Scholar 

  93. Shukla VK, Lemaire S. Non-opioid effects of dynorphins: possible role of the NMDA receptor. Trends Pharmacol Sci 1994;15:420–4.

    PubMed  CAS  Google Scholar 

  94. Caudle RM, Mannes AJ. Dynorphin: friend or foe? Pain 2000;87:235–9.

    PubMed  CAS  Google Scholar 

  95. Lai J, Ossipov M, Vanderah TW, Malan TP Jr, Porreca F. Neuropathic pain: the paradox of dynorphin. Mol Interv 2001;1:160–7.

    PubMed  CAS  Google Scholar 

  96. Hauser KF, Aldrich JV, Anderson KJ, Bakalkin G, Christie MJ, Hall ED, Knapp PE, Scheff SW, Singh IN, Vissel B, Woods AS, Yakovleva T, Shippenberg TS. Pathobiology of dynorphins in trauma and disease. Front Biosci 2005;10:216–35.

    PubMed  CAS  Google Scholar 

  97. Hauser KF, Knapp PE, Tyrbek CS. Structure–activity analysis of dynorphin A toxicity in spinal cord neurons: intrinsic neurotoxicity of dynorphin A and its carboxyl-terminal, nonopioid metabolites. Exp Neurol 2001;168:78–87.

    PubMed  CAS  Google Scholar 

  98. Naqvi T, Haq W, Mathur KB. Structure–activity relationship studies of dynorphin A and related peptides. Peptides 1998;19:1277–92.

    PubMed  CAS  Google Scholar 

  99. Choi H, Murray TF, DeLander GE, Schmidt WK, Aldrich JV. Synthesis and opioid activity of [D-Pro10]dynorphin A-(1-11) analogues with N-terminal alkyl substitution. J Med Chem 1997;40:2733–9.

    PubMed  CAS  Google Scholar 

  100. Gairin JE, Mazarguil H, Alvinerie P, Botanch C, Cros J, Meunier J-C. N,N-Diallyl-tyrosyl substitution confers antagonist properties on the κ-selective opioid peptide [D-Pro10]-dynorphin A-(1-11). Br J Pharmacol 1988;95:1023–30.

    PubMed  CAS  Google Scholar 

  101. Soderstrom K, Choi H, Aldrich JV, Murray TF. N-Alkylated derivatives of [D-Pro10]dynorphin A-(1–11) are high affinity partial agonists at the cloned rat κ-opioid receptor. Eur J Pharmacol 1997;338:191–7.

    PubMed  CAS  Google Scholar 

  102. Lung F-DT, Meyer J-P, Lou B-S, Xiang L, Li G, Davis P, De Leon IA, Yamamura HI, Porreca F, Hruby VJ. Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on κ receptor selectivity and potency. J Med Chem 1996;39:2456–60.

    PubMed  CAS  Google Scholar 

  103. Schlechtingen G, Zhang L, Maycock A, DeHaven RN, Daubert JD, Cassel J, Chung NN, Schiller PW, Goodman M. [Pro3]Dyn A(1-11)NH2: a dynorphin analogue with high selectivity for the κ opioid receptor. J Med Chem 2000;43:2698–702.

    PubMed  CAS  Google Scholar 

  104. Lemaire S, Lafrance L, Dumont M. Synthesis and biological activity of dynorphin-(1-13) and analogs substituted in positions 8 and 10. Int J Pept Protein Res 1986;27:300–5.

    PubMed  CAS  Google Scholar 

  105. Meyer JP, Gillespie TJ, Hom S, Hruby VJ, Davis TP. In vitro stability of some reduced peptide bond pseudopeptide analogues of dynorphin A. Peptides 1995;16:1215–9.

    PubMed  CAS  Google Scholar 

  106. Hiramatsu M, Inoue K, Ambo A, Sasaki Y, Kameyama T. Long-lasting antinociceptive effects of a novel dynorphin analogue, Tyr-D-Ala-Phe-Leu-Arg¬(CH2NH)Arg-NH2, in mice. Br J Pharmacol 2001;132:1948–56.

    PubMed  CAS  Google Scholar 

  107. Yoshino H, Nakazawa T, Arakawa Y, Kaneko T, Tsuchiya Y, Matsunaga M, Araki S, Ikeda M, Yamatsu K, Tachibana S. Synthesis and structure–activity relationships of dynorphin A-(1-8) amide analogues. J Med Chem 1990;33:206–12.

    PubMed  CAS  Google Scholar 

  108. Yu J, Butelman ER, Woods JH, Chait BT, Kreek MJ. Dynorphin A (1-8) analog, E-2078, crosses the blood–brain barrier in rhesus monkeys. J Pharmacol Exp Ther 1997;282:633–8.

    PubMed  CAS  Google Scholar 

  109. Butelman ER, Vivian JA, Yu J, Kreek MJ, Woods JH. Systematic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys. Psychopharmacology (Berl) 1999;143:190–6.

    CAS  Google Scholar 

  110. Butelman ER, Harris T, Kreek MJ. Effects of E-2078, a stable dynorphin A(1-8) analog, on sedation and serum prolactin levels in rhesus monkey. Psychopharmacology (Berl) 1999;147:73–80.

    CAS  Google Scholar 

  111. Ohnishi A, Mihara M, Yasuda S, Tomono Y, Hasegawa J, Tanaka T. Aquaretic effect of the stable dynorphin-A analog E2078 in the human. J Pharmacol Exp Ther 1994;270:342–7.

    PubMed  CAS  Google Scholar 

  112. Fujimoto K, Momose T. Analgesic efficacy of E-2078 (dynorphin analog) in patients following abdominal surgery. Jap J Anesth 1995;44:1233–7.

    CAS  Google Scholar 

  113. Terasaki T, Deguchi Y, Sato H, Hirai K, Tsuji A. In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood–brain-barrier—an application of brain microdialysis. Pharmaceut Res 1991;8:815–20.

    CAS  Google Scholar 

  114. Nakazawa T, Furuya Y, Kaneko T, Yamatsu K. Spinal kappa-receptor-mediated analgesia of E-2078, a systemically active dynorphin analog, in mice. J Pharmacol Exp Ther 1991;256:76–81.

    PubMed  CAS  Google Scholar 

  115. Nakazawa T, Kaneko T, Yoshino H, Tachibana S, Goto M, Taki T, Yamatsu K. Physical-dependence liability of dynorphin-A analogs in rodents. Eur J Pharmacol 1991;201:185–9.

    PubMed  CAS  Google Scholar 

  116. Salas SP, Roblero JS, Lopez LF, Tachibana S, Huidobro-Toro JP. [N-Methyl-Tyr1,N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8)ethylamide, a stable dynorphin analog, produces diuresis by kappa-opiate receptor activation in the rat. J Pharmacol Exp Ther 1992;262:979–86.

    PubMed  CAS  Google Scholar 

  117. Al-Fayoumi SI, Brugos B, Arya V, Mulder E, Eppler B, Mauderli AP, Hochhaus G. Identification of stabilized dynorphin derivatives for suppressing tolerance in morphine-dependent rats. Pharm Res 2004;21:1450–6.

    PubMed  CAS  Google Scholar 

  118. Brugos B, Arya V, Hochhaus G. Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: effect of different routes of administration. AAPS J 2004;6:e36.

    PubMed  Google Scholar 

  119. Aldrich JV, Patkar KA, Chappa AK, Fang W, Audus KL, Lunte SM, Carey AN, McLaughlin JP. Development of centrally acting peptide analogs: structure-transport studies and pharmacological evaluation of analogs of the opioid peptide dynorphin A. In: Wilce J, editor. Proceedings of the 4th International Peptide Symposium. 2008, www.peptidoz.org, M 64.

  120. Dando PM, Brown MA, Barrett AJ. Human thimet oligopeptidase. Biochem J 1993;294(Pt 2):451–7.

    PubMed  CAS  Google Scholar 

  121. Turner TD, Browning JL, Widmayer MA, Baskin DS. Penetration of dynorphin 1-13 across the blood–brain barrier. Neuropeptides 1998;32:141–9.

    PubMed  CAS  Google Scholar 

  122. Terasaki T, Hirai KI, Sato H, Kang YS, Tsuji A. Absorptive-mediated endocytosis of a dynorphin-like analgesic peptide, E-2078, into the blood–brain barrier. J Pharmacol Exp Ther 1989;251:351–7.

    PubMed  CAS  Google Scholar 

  123. Witt KA, Davis TP. CNS drug delivery: opioid peptides and the blood-brain barrier. AAPS J 2006;8:E76–88.

    PubMed  CAS  Google Scholar 

  124. Pan W, Kastin AJ. Polypeptide delivery across the blood–brain barrier. Curr Drug Targets CNS Neurol Disord 2004;3:131–6.

    PubMed  CAS  Google Scholar 

  125. Dooley CT, Ny P, Bidlack JM, Houghten RA. Selective ligands for the μ, δ, and κ opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library. J Biol Chem 1998;273:18848–56.

    PubMed  CAS  Google Scholar 

  126. Schteingart CD, Menzaghi F, Jiang G, Alexander RV, Sueiras-Diaz J, Spencer RH, Chalmers DT, Luo Z. (2008) Synthetic peptide amides. US Patent 7,402,564, Cara Therapeutics, Inc.

  127. Wan Q, Murray TF, Aldrich JV. A novel acetylated analogue of dynorphin A-(1-11) amide as a κ opioid receptor antagonist. J Med Chem 1999;42:3011–3.

    PubMed  CAS  Google Scholar 

  128. Lu Y, Nguyen TM-D, Weltrowska G, Berezowska I, Lemieux C, Chung NN, Schiller PW. [2′,6′-Dimethyltyrosine]dynorphin A(1-11)NH2 analogues lacking an N-terminal amino group: potent and selective κ opioid antagonists. J Med Chem 2001;44:3048–53.

    PubMed  CAS  Google Scholar 

  129. Bennett MA, Murray TF, Aldrich JV. Identification of arodyn, a novel acetylated dynorphin A-(1-11) analogue, as a κ opioid receptor antagonist. J Med Chem 2002;45:5617–9.

    PubMed  CAS  Google Scholar 

  130. Vig BS, Murray TF, Aldrich JV. A novel N-terminal cyclic dynorphin A analogue cyclo N,5[Trp3,Trp4,Glu5]dynorphin A-(1–11)-NH2 that lacks the basic N-terminus. J Med Chem 2003;46:1279–82.

    PubMed  CAS  Google Scholar 

  131. Patkar KA, Yan X, Murray TF, Aldrich JV. [Nα-BenzylTyr1-cyclo(D-Asp5,Dap8)]-dynorphin A-(1–11)NH2 cyclized in the “address” domain is a novel kappa-opioid receptor antagonist. J Med Chem 2005;48:4500–3.

    PubMed  CAS  Google Scholar 

  132. Saito T, Hirai H, Kim Y-J, Kojima Y, Matsunaga Y, Nishida H, Sakakibara T, Suga O, Sujaku T, Kojima N. CJ-15208, a novel kappa opioid receptor antagonist, from a fungus, Ctenomyces serratus ATCC15502. J Antibiot 2002;55:847–54.

    PubMed  CAS  Google Scholar 

  133. Marx M. Watching peptide drugs grow up. Chem Eng News 2005;83:17–24.

    Google Scholar 

  134. Zhao K, Luo G, Zhao GM, Schiller PW, Szeto HH. Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther 2003;304:425–32.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by grants R01 DA018832, R01 DA023924, and K02 DA000393 (JVA) from the National Institute on Drug Abuse and by the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development (JPM).

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Correspondence to Jane V. Aldrich.

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Guest Editors: Rao Rapaka and Vishnu Purohit

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Aldrich, J.V., McLaughlin, J.P. Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development. AAPS J 11, 312–322 (2009). https://doi.org/10.1208/s12248-009-9105-4

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