Opioids pp 547-584 | Cite as

Peptidase Inactivation of Enkephalins: Design of Inhibitors and Biochemical, Pharmacological, and Clinical Applications

  • B. P. Roques
  • A. Beaumont
  • V. Dauge
  • M.-C. Fournié-Zaluski
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 1)


Because of their critical role in various adaptational processes, extensive pharmacological studies have been devoted to the neuropeptides, a family of chemical messengers acting in the central nervous system as neurotransmitters and/or neuromodulators. This is particularly true for the opioid peptides, which are involved in the control of pain and modulation of mood through their interaction with different classes of binding sites.


Angiotensin Converting Enzyme Opioid Receptor Atrial Natriuretic Peptide Neutral Endopeptidase Mixed Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Algeri S, Altstein M, Blumberg S, de Simoni GM, Guardabasso V (1981) In vivo potentiation of [D-Ala2] Met-enkephalin amide central effects of the administration of an enképhalinase inhibitor. Eur J Pharmacol 74: 261–262Google Scholar
  2. Almenoff J, Orlowski M (1983) Membrane-bound kidney neutral metalloendo- peptidase: Interaction with synthetic substrates, natural peptides and inhibitors. Biochemistry 22: 590–599Google Scholar
  3. Almenoff J, Orlowski M (1984) Biochemical and immunological properties of a membrane-bound brain metalloendopeptidase: comparison with thermolysin- like kidney neutral metalloendopeptidase. J Neurochem 42: 151–157PubMedGoogle Scholar
  4. Altstein M, Blumberg S, Vogel Z (1982) Phosphoryl-Leu-Phe: a potent inhibitor of the degradation of enkephalin by enképhalinase. Eur J Pharmacol 76: 299–300Google Scholar
  5. Altstein M, Bacher E, Vogel Z, Blumberg S (1983) Protection of enkephalins from enzymatic degradation utilizing selective metal-chelating inhibitors. Eur J Pharmacol 91: 353–361PubMedGoogle Scholar
  6. Aoki K, Kajiwara M, Oka T (1984) The role of bestatin sensitive aminopeptidase, angiotensin converting enzyme and thiorphan sensitive “enképhalinase” in the potency of enkephalins in the guinea-pig ileum. Jpn J Pharmacol 36: 59–65PubMedGoogle Scholar
  7. Baamonde A, Daugé V, Ruiz-Gayo M, Fulga IG, Turcaud S, Fournié-Zaluski MC, Roques BP (1992) Antidepressant-type effects of endogenous enkephalins protected by systemic RB101 are mediated by opioid δ and D1 dopamine receptor stimulation. Eur J Pharmacol (in press)Google Scholar
  8. Back SA, Gorenstein C (1989) Histochemical visualization of neutral endopeptidase- 24.11 (enképhalinase) activity in rat brain: cellular localization and codistribution with enkephalins in the globus pallidus. J Neurosci 9: 4439–4455PubMedGoogle Scholar
  9. Bado A, Roze C, Lewin JM, Dubrasquet M (1989) Endogenous opioid peptides in the control of food intake in cats. Peptide 10: 967–971Google Scholar
  10. Barnes K, Turner AJ, Kenny AJ (1988) Electronmicroscopic immunocytochemistry of pig brain shows that endopeptidase–24.11 is localized in neuronal membranes. Neurosci Lett 94: 64–69PubMedGoogle Scholar
  11. Bateman RC, Jackson D, Slaughter CA, Unnithan S, Chai YG, Moomaw C, Hersh LB (1989) Identification of the active–site arginine in rat neutral endopeptidase 24.11 (enképhalinase) as arginine 102 and analysis of a glutamine 102 mutant. J Biol Chem 264: 6151–6157PubMedGoogle Scholar
  12. Beaumont A, Brouet JC, Roques BP (1989) Neutral endopeptidase 24.11 and angiotensin converting enzyme like activity in CALLA positive and CALLA negative lymphocytes. Biochem Biophys Res Commun 160: 1323–1329PubMedGoogle Scholar
  13. Beaumont A, Le Moual H, Boileau G, Crine P, Roques BP (1991) Evidence that both arginine 102 and arginine 747 are involved in substrate binding to neutral endopeptidase-24.11. J Biol Chem 266: 214–220PubMedGoogle Scholar
  14. Ben Natan L, Chaillet P, Lecomte JM, Marcais H, Uchida G, Costentin J (1984) Involvement of endogenous enkephalins in the mouse “behavioral despair’1 test. Eur J Pharmacol 97: 301–304PubMedGoogle Scholar
  15. Benchetrit T, Fournié-Zaluski MC, Roques BP (1987) Relationship between the inhibitory potencies of thiorphan and retrothiorphan enantiomers on thermolysin and neutral endopeptidase 24.11 and their interactions with the thermolysin active site by computer modelling. Biochem Biophys Res Commun 147: 1034–1040Google Scholar
  16. Benchetrit T, Fournié-Zaluski MC, Roques BP (1987) Relationship between the inhibitory potencies of thiorphan and retrothiorphan enantiomers on thermolysin and neutral endopeptidase 24.11 and their interactions with the thermolysin active site by computer modelling. Biochem Biophys Res Commun 147: 1034–1040PubMedGoogle Scholar
  17. Benuck M, Mark N (1979) Co-identity of brain angiotensin converting enzyme with a membrane bound dipeptidyl carboxypeptidase inactivating met-enkephalin. Biochem Biophys Res Commun 88: 215–221PubMedGoogle Scholar
  18. Blumberg S, Vogel Z, Altstein M (1981) Inhibition of encephalin-degrading enzymes from rat brain and of thermolysin by amino acid hydroxamates. Life Sci 28: 301–306PubMedGoogle Scholar
  19. Bouboutou R, Waksman G, Devin J, Fournié-Zaluski MC, Roques BP (1984) Bidentate peptides: highly potent new inhibitors of enkephalin degrading enzymes. Life Sci 35: 1023–1030PubMedGoogle Scholar
  20. Boudinot E, Denavit–Saubie M, Fournié-Zaluski MC, Morin-Surun MP, Roques BP (1988) Respiratory consequences in cats and rats of inhibition of encephalin- degrading enzymes by kelatorphan. J Physiol 406. 169 PGoogle Scholar
  21. Bourgoin S, Le Bars D, Artaud F, Clot AM, Bouboutou R, Fournié-Zaluski MC, Roques BP, Hamon M, Cesselin F (1986) Effects of kelatorphan and other peptidase inhibitors on the in vitro and in vivo release of methionine-encephalin- like material from the rat spinal cord. J Pharmacol Exp Ther 238: 360–366PubMedGoogle Scholar
  22. Butcher SP, Varro A, Kelly JS, Dockray GJ (1989) In vivo studies on the enhancement of cholecystokinin release in the rat striatum by dopamine depletion. Brain Res 505: 119–122PubMedGoogle Scholar
  23. Calenco-Choukroun G, Daugé V, Gacel G, Féger J, Roques BP (1991) Opioid δ-agonists and endogenous enkephalins induce different emotional reactivity than μ-agonists after injection in the rat ventral tegmental area. Psycho- pharmacology 103: 493–502Google Scholar
  24. Carenzi A, Frigeni V, Delia-Bella D (1981) Strong analgesic effect of Leu-enkephalin after inhibition of brain aminopeptidases: a pharmacological study. In: Takagi H, Simon EF (eds) Advances in endogenous and exogenous opioids, proceedings of the international Narcotic Research Conference, Kyoto, p 267Google Scholar
  25. Carenzi A, Frigeni V, Reggiani A, Delia-Bella D (1983) Effect of inhibition of neuropeptidases on the pain threshold of mice and rats. Neuropharmacology 22: 1315–1319PubMedGoogle Scholar
  26. Cesselin F, Oliveras JL, Bourgoin S, Sierralta F, Michelot R, Besson JM, Hamon M (1982) Increased levels of Met-enkephalin like material in the CSF of anesthetized cats after tooth pulp stimulation. Brain Res 237: 325 - 338PubMedGoogle Scholar
  27. Cesselin F, Benoleil JJ, Bourgoin S, Mauborgne A, Hamon M (1989) Effects of opioid receptor agonists on the in vitro release of CCK-8 like material from the rat substantia nigra and spinal cord. Adv Biosc 75: 205–208Google Scholar
  28. Chaillet P, Marçais-Collado H, Costentin J, Yi CC, de la Baume S, Schwartz JC (1983) Inhibition of enkephalin metabolism and antinociceptive activity of, bestatin, an aminopeptidase inhibitor. Eur J Pharmacol 86: 329–336Google Scholar
  29. Chaillet P, Coulaud A, Zajac JM, Fournié-Zaluski MC, Costentin J, Roques BP (1984) The mu rather than the delta subtype of opioid receptors appears to be involved in enkephalin induced analgesia. Eur J Pharmacol 101: 83–90PubMedGoogle Scholar
  30. Chan WWC (1983) L-Leucinethiol - a potent inhibitor of leucine aminopeptidase. Biochem Biophys Res Commun 116: 297–302PubMedGoogle Scholar
  31. Chaussade S, Hamm R, Lecomte JM, Couturier D, Guerre J (1988) Effects of an enképhalinase inhibitor on oesophageal motility in man. Gastroenterol Clin Biol 12: 793–796PubMedGoogle Scholar
  32. Checler F, Vincent JP, Kitabgi P (1983) Degradation of neurotensin by rat brain synaptic membranes involvement of a thermolysin like metalloendopeptidase (enképhalinase), angiotensin converting enzyme, and other unidentified peptides. J Neurochem 41: 375–384PubMedGoogle Scholar
  33. Chérot P, Devin J, Fournié-Zaluski MC, Roques BP (1986a) Enkephalin degrading dipeptidylaminopeptidase: characterization of the active site and selective inhibition. Mol Pharmacol 30: 338–344PubMedGoogle Scholar
  34. Chérot P, Fournié-Zaluski MC, Laval J (1986b) Purification and characterization of an encephalin-degrading dipeptidyl-aminopeptidase from porcine brain. Biochemistry 25: 8184–8191PubMedGoogle Scholar
  35. Chipkin RE (1986) Inhibitors of enképhalinase: the next generation of analgesics. In: Drug of the future, vol 11, pp 593–607Google Scholar
  36. Chipkin RE, Latranyi MZ, Iorio LC (1982a) Potentiation of stress–induced analgesia ( SIA) by thiorphan and its block by naloxone. Life Sci 31: 1189–1192Google Scholar
  37. Chipkin RE, Latranyi MZ, Iorio LC, Barnett A (1982b) Potentiation of [D-Ala2] enkephalinamide analgesia in rats by thiorphan. Eur J Pharmacol 83: 283–288PubMedGoogle Scholar
  38. Chipkin RE, Berger JG, Billard W, Iorio LC, Chapman R, Barnett A (1988) Pharmacology of SCH 34826, an orally active enképhalinase inhibitor analgesic. J Pharmacol Exp Ther 245: 829–838PubMedGoogle Scholar
  39. Costentin J, Valiculescu A, Chaillet P, Ben Natan L, Aveaux D, Schwartz JC (1986) Dissociated effects of inhibitors of enkephalin-metabolising peptidases or naloxone on various nociceptive responses. Eur J Pharmacol 123: 37–44PubMedGoogle Scholar
  40. Coulter HD (1988) Vesicular localisation immunoreactive [Met5]enkephalin in the globus pallidus. Proc Natl Acad Sci USA 85: 7028–7032PubMedGoogle Scholar
  41. Craves FB, Law PY, Hunt CA, Loh HH (1978) The metabolic disposition of radiolabeled enkephalins in vitro and in situ. J Pharmacol Exp Ther 206: 492–506PubMedGoogle Scholar
  42. Cuello AC (1983) Central distribution of opioid peptides. Br Med Bull 33: 11–17Google Scholar
  43. D’Adamio L, Shipp MA, Masteller EL, Reinherz EI (1989) Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5’ untranslated regions. Proc Natl Acad Sci USA 86: 7103–7107PubMedGoogle Scholar
  44. Daugé V, Rossignol P, Roques BP (1988) Comparison of the behavioural effects induced by administration in rat nucleus accumbens or nucleus caudatus of selective [i and 5 opioid peptides or kelatorphan, an inhibitor of encephalin- degrading enzymes. Psychopharmacology 96: 343–352PubMedGoogle Scholar
  45. Daugé V, Rossignol P, Roques BP (1989) Blockade of dopamine receptors reverse the behavioral effects of endogenous enkephalins in the nucleus caudatus but not in the nucleus accumbens: differential involvement of δ and μ opioid receptors. Psychopharmacology 99: 168–175PubMedGoogle Scholar
  46. Del Carmen de Felipe M, Jimenez I, Castro A, Fuentes JA (1989) Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of encephalin-degrading peptidases. Eur J Pharmacol 159: 175–180Google Scholar
  47. Del Fiacco M, Paxinos G, Cuello AC (1982) Neostriatal encephalin-immmunoreactive neurons project to the globus pallidus. Brain Res 231: 1–17PubMedGoogle Scholar
  48. Delay-Goyet P, Zajac JM, Javoy-Agid F, Agid Y, Roques BP (1987) Regional distribution of μ, δ and ĸ opioid receptors in human brain from controls and parkinsonian subjects. Brain Res 414: 8–14PubMedGoogle Scholar
  49. Devault A, Lazure C, Nault C, Le Moual H, Seidah NG, Chretien M, Kahn P, Powell J, Mallet J, Beaumont A, Roques BP, Crine P, Boileau C (1987) Amino acid sequence of rabbit kidney neutral endopeptidase 24.11 (enképhalinase) deduced from a complementary DNA. EMBO J 6: 1317–1322PubMedGoogle Scholar
  50. Devault A, Nault C, Zollinger M, Fournié-Zaluski MC, Roques BP, Crine P, Boileau G (1988) Expression of neutral endopeptidase (enképhalinase) in heterologous cos-1 cells: characterization of the recombinant enzyme and evidence for a glutamic acid residue at the active site. J Biol Chem 263: 4033–4040PubMedGoogle Scholar
  51. De Witte P, Heidbreder C, Roques BP (1989) Kelatorphan, a potent enképhalinase inhibitor, and opioid receptor agonists DAGO and DTLET, differentially modulate self-stimulation behaviour depending on the site of administration. Neuropharmacology 28: 667–676PubMedGoogle Scholar
  52. Dickenson AH (1986) Enkephalins. A new approach to pain relief? Nature 320: 681–682PubMedGoogle Scholar
  53. Dickenson AH, Sullivan A, Feeney C, Fournié-Zaluski MC, Roques BP (1986) Evidence that endogenous enkephalins produce δ-opiate receptor mediated neuronal inhibitions in rat dorsal horn. Neurosci Lett 72: 179–182PubMedGoogle Scholar
  54. Dickenson AH, Sullivan AF, Fournié-Zaluski MC, Roques BP (1987) Prevention of degradation of endogenous enkephalins produces inhibition of nociceptive neurones in rat spinal cord. Brain Res 408: 185–191PubMedGoogle Scholar
  55. Dickenson AH, Sullivan AF, Roques BP (1988) Evidence that endogenous enkephalins and a d opioid receptor agonist have a common site of action in spinal antinociception. Eur J Pharmacol 148: 437–439PubMedGoogle Scholar
  56. Dzoljic MR, Ukponmwan OE, Rupreht J, Haffman J (1985) Role of the enkephalinergic system in sleep studies by an enképhalinase inhibitor. In: Vauquier A (ed) Sleep: neurotransmitters and neuromodulators. Raven, New York, p 251Google Scholar
  57. Dzoljic TD, Nadel JA, Dusser DJ, Sekizawa K, Graf PD, Borson DB (1989) Inhibitors of neutral endopeptidase potentiate electrically and capsaicin-induced noncholinergic contraction in guinea pig bronchi. J Pharmacol Exp Ther 248: 7–11Google Scholar
  58. Dourmap N, Michael-Titus A, Costentin J (1990) Local enkephalins tonically modulate dopamine release in the striatum: a microdialysis study. Brain Res 524: 153–155PubMedGoogle Scholar
  59. Dupont A, Cusan L, Garon M, Alvarado-Urbina G, Labrie F (1977) Extremely rapid degradation of [3H]-methionine enkephalin by various rat tissues in vivo and in vitro. Life Sci 21: 907–914PubMedGoogle Scholar
  60. Durieux C, Charpentier B, Fellion E, Gacel G, Pelaprat D, Roques BP (1985) Multiple cleavage sites of cholecystokinin heptapeptides by enképhalinase. Peptides 6: 495–501PubMedGoogle Scholar
  61. Durieux C, Charpentier D, Pelaprat D, Roques BP (1986) Investigation on the metabolism of CCK8 analogues by rat brain slices. Neuropeptides 7: 1–9PubMedGoogle Scholar
  62. Dusser DJ, Jocoby DB, Djokil TD, Rubinstein F, Borson DB, Nadel JA (1989) Virus induces airway hyperresponsiveness to tachykinins: role of neutral endopeptidase. J Appl Physiol 67: 1504–1511PubMedGoogle Scholar
  63. Elliot RL, Marks N, Berg MJ, Portoghese PS (1985) Synthesis and biological evaluation of phosphonomidate peptide inhibitors of enképhalinase and angiotensin converting enzyme. J Med Chem 28: 1208–1216Google Scholar
  64. Erdos EG, Skidgel RA (1989) Neutral endopeptidase 24.11 (enképhalinase) and related regulators of peptide hormones. FASEB J 3: 145–151PubMedGoogle Scholar
  65. Erdos EG, Johnson AR, Boyden NT (1978) Hydrolysis of enkephalin by cultured human endothelial cells and by purified peptidyl dipeptidase. Biochem Pharmacol 27: 843–845PubMedGoogle Scholar
  66. Floras P, Bidabe AM, Vaille JM, Simonnet G, Lecomte JM, Sabathie M (1983) Double-blind study of effects of enképhalinase inhibitor on adverse reactions to myelography. Am J Neuroradiol 4: 653–655PubMedGoogle Scholar
  67. Florentin D, Sassi A, Roques BP (1984) A highly sensitive fluorimetric assay for “enképhalinase”, a neutral metalloendopeptidase that releases Tyr-Gly-Gly from enkephalins. Anal Biochem 141: 62–69PubMedGoogle Scholar
  68. Fournié-Zaluski MC, Perdrisot R, Gacel G, Swerts JP, Roques BP, Schwartz JC (1979) Inhibitory potency of various peptides on enképhalinase activity from mouse striatum. Biochem Biophys Res Commun 91: 130–135PubMedGoogle Scholar
  69. Fournié-Zaluski MC, Llorens C, Gacel G, Malfroy B, Swerts JP, Lecomte JM, Schwartz JC, Roques BP (1981) Synthesis and biological properties of highly potent enképhalinase inhibitors. In: Brunfeld K (ed) Peptides 1980. Scriptor, Copenhagen, pp 476–481Google Scholar
  70. Fournié-Zaluski MC, Soroca-Lucas E, Waksman G, Llorens C, Schwartz JC, Roques BP (1982) Differential recognition of “enképhalinase” and angiotensin– converting–enzyme by new carboxyalkyl inhibitors. Life Sci 31: 2947–2954PubMedGoogle Scholar
  71. Fournié-Zaluski MC, Chaillet P, Soroca-Lucas E, Costentin J, Roques BP (1983) New carboxyalkyl inhibitors of brain “enképhalinase”: synthesis, biological activity and analgesic properties. J Med Chem 26: 60–65PubMedGoogle Scholar
  72. Fournié-Zaluski MC, Lucas E, Waksman G, Roques BP (1984a) Differences in the structural requirements for selective interaction with neutral metalloendopeptidase (enképhalinase) or angiotensin converting enzyme: molecular investigation by use of new thiol inhibitors. Eur J Biochem 139: 267–274PubMedGoogle Scholar
  73. Fournié-Zaluski MC, Chaillet P, Bouboutou R, Coulaud A, Chérot P, Waksman G, Costentin J, Roques BP (1984b) Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. Eur J Pharmacol 102: 525–528PubMedGoogle Scholar
  74. Fournié-Zaluski MC, Coulaud A, Bouboutou R, Chaillet P, Devin J, Waksman G, Costentin J, Roques BP (1985) New bidentates as full inhibitors of enkephalin degrading enzymes: synthesis and analgesic properties. J Med Chem 28: 1158–1169PubMedGoogle Scholar
  75. Fournié-Zaluski MC, Soleihac JM, Turcaud S, Lai-Kuen R, Crine P, Beaumont A, Roques BP (1992) Development of [125I]RB104, a new potent inhibitor of neutral endopeptidase–24,11 and its use in detecting nanogram quantities of the enzyme by “Inhibitor Gel Electrophoresis.” Proc Natl Acad Sci USA (in press)Google Scholar
  76. Gacel G, Fournié-Zaluski MC, Fellion E, Roques BP (1981) Evidence of the preferential involvement of μ-receptors in analgesia using enkephalins highly selective for peripheral (μ or δ receptors. J Med Chem 24: 1119–1124PubMedGoogle Scholar
  77. Gee NS, Bowes MA, Buck P, Kenny AJ (1985) An immunoradiometric assay for endopeptidase 24–11 shows it to be a widely distributed enzyme in pig tissues. Biochem J 228: 119–126PubMedGoogle Scholar
  78. Gibert-Rahola J, Tejedor P, Chover AJ, Puyana M, Rodriguez MM, Leonsegui I, Mellado M, Mico JA, Maldonado R, Roques BP (1990) RB38B, a selective neutral endopeptidase inhibitor, induced reversal of escape deficits caused by inescapable shocks pretreatment in rats. In: Van Ree JM, Mulder AH, Wiegant VM, Van Wimersma Greidanus TB (eds) New leads in opioid research. Excerpta Medica, Amsterdam, p 2317Google Scholar
  79. Glimcher PW, Giovino AA, Margolin DH, Hoebel BG (1984) Endogenous opiate reward induced by an enkephalinergic inhibitor, thiorphan, injected into the ventral midbrain. Behav Neurosci 98: 262–268PubMedGoogle Scholar
  80. Gordon EM, Cushman DW, Tung R, Cheung HS, Wang FL, Delaney NG (1983) Rat brain enképhalinase: characterization of the active site using mercapto-propanoyl amino acid inhibitors and comparison with angiotensin-converting enzyme. Life Sci 33: 113–116PubMedGoogle Scholar
  81. Gordon EM, Godfrey JD, Delaney NG, Asaad MM, Von Langen D, Cushman DW (1988) Design of novel inhibitors of aminopeptidases, synthesis of peptide- derived diamino thiols and sulfur replacement analogues of bestatin. J Med Chem 31: 2199–2211PubMedGoogle Scholar
  82. Gorenstein C, Snyder SH (1979) Two distinct enképhalinases: solubilization, partial purification and separation from angiotensin converting enzyme. Life Sci 25: 2065–2070PubMedGoogle Scholar
  83. Gros C, Giros B, Schwartz JC (1985) Identification of aminopeptidase M as an enkephalin–inactivating enzyme in rat cerebral membranes. Biochemistry 24: 2179–2186PubMedGoogle Scholar
  84. Gros C, Giros B, Schwartz JC, Vlaiculescu A, Costentin J, Lecomte JM (1988) Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound. Neuropeptides 12: 111–118PubMedGoogle Scholar
  85. Gros C, Souque A, Schwartz JC, Duchier J, Cournot A, Baumer P, Lecomte JM (1989) Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enképhalinase (EC by acetorphan. Proc Natl Acad Sci USA 86: 7580–7584PubMedGoogle Scholar
  86. Guyon A, Roques BP, Foucaud A, Guyon F, Caude M, Perdrisot R, Schwartz JC (1979) Enkephalin degradation in mouse brain studied by a new HPLC method: further evidence for the involvement of a carboxypeptidase. Life Sci 25:1605–1612Google Scholar
  87. Hachisu M, Takahashi H, Hiranuma T, Shibazaki Y, Murata S (1985) Relationship between enképhalinase inhibition of thiorphan in vivo and its analgesic activity. J Pharmacobiodyn 8: 701–710PubMedGoogle Scholar
  88. Haffmans J, Dzoljic MR (1987) Inhibition of enképhalinase activity attenuates naloxone–precipitated withdrawal symptoms. Gen Pharmacol 18: 103–105PubMedGoogle Scholar
  89. Hambrook JM, Morgan BA, Ranee MJ, Smith CFC (1976) Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates. Nature 262: 782–783PubMedGoogle Scholar
  90. Hamel E, Beaudet A (1987) Opioid receptors in rat neostriatum: radioautographic distribution at the electron microscopic level. Brain Res 401: 239–257PubMedGoogle Scholar
  91. Helene A, Beaumont A, Roques BP (1991) Functional residues at the active site of aminopeptidase N. Eur J Biochem 196: 385–393Google Scholar
  92. Hernandez JF, Soleihac JM, Roques BP, Fournié-Zaluski MC (1988) Retro–inverso concept applied to the mixed inhibitors of enkephalin–degrading enzymes. J Med Chem 31: 1825–1831PubMedGoogle Scholar
  93. Hersh LB (1981) Solubilization and characterization of two rat brain amino-peptidases active on Metenkephalin. Biochemistry 20: 2345–2350PubMedGoogle Scholar
  94. Hersh LB, Morihara K (1986) Comparison of the subsite specificity of the mammalian neutral endopeptidase 24–11 (enképhalinase) to the bacterial neutral endopeptidase thermolysin. J Biol Chem 261: 6433–6437PubMedGoogle Scholar
  95. Hersh LB, Aboukhair N, Watson S (1987) Immunohistochemical localization of aminopeptidase M in rat brain and periphery: relationship of enzyme localization and enkephalin metabolism. Peptides 8: 523–532PubMedGoogle Scholar
  96. Horsthemke B, Hamprecht B, Bauer K (1983) Heterogenous distribution of encephalin-degrading peptidases between neuronal and glial cells. Biochem Biophys Res Commun 115: 423–429PubMedGoogle Scholar
  97. Hudgin RL, Charlson SE, Zimmerman M, Mumford R, Wood PL (1981) Enképhalinase: selective peptide inhibitors. Life Sci 29: 2593–2601PubMedGoogle Scholar
  98. Hui KS, Wang YJ, Lajtha A (1983) Purification and characterization of an enkephalin aminopeptidase from rat brain membranes. Biochemistry 22: 1062–1067PubMedGoogle Scholar
  99. Jessell TM, Iversen LL (1977) Opiates analgesic inhibit substance P release from rat trigeminal nucleus. Nature 268: 549–551PubMedGoogle Scholar
  100. Jivegard L, Pollard H, Moreau J, Schwartz JC, Thune A, Svanik J (1989) Naloxone- reversible inhibition of gall-bladder mucosa fluid secretion in experimental cholecystities in the cat by acetorphan, an enképhalinase inhibitor. Clin Sci 77: 49–54PubMedGoogle Scholar
  101. Jongeneel CV, Bouvier J, Bairoch A (1989) A unique signature identifies a family of zinc-dependent metallopeptidase. FEBS Lett 242: 211–214PubMedGoogle Scholar
  102. Kalivas PW (1985) Interactions between neuropeptides and dopamine neurons in the ventro-medial mesencephalon. Neurosci Behav Rev 9: 573–587Google Scholar
  103. Kalivas PW, Richardson-Carlson R, Van Orden G (1986) Cross-sensitization between foot shock stress and encephalin-induced motor activity. Biol Psychiatry 21: 939–950PubMedGoogle Scholar
  104. Kayser V, Benoist JM, Gautron M, Guilbaud G, Roques BP (1984) Effects of ES52 an enképhalinase inhibitor, on responses of ventrobasal thalamic neurons in rat. Peptides 5: 1159–1164PubMedGoogle Scholar
  105. Kayser V, Fournié-Zaluski MC, Guilbaud G, Roques BP (1989) Potent anti-nociceptive effects of kelatorphan (a highly efficient inhibitor of multiple enkephalin degrading enzymes) systemically administered in normal and arthritic rats. Brain Res 497: 94–101PubMedGoogle Scholar
  106. Kenny AJ (1986) Cell surface peptidases are neither peptide- nor organ-specific. Trends Biochem Sci 11: 40–42Google Scholar
  107. Kenny AJ, Stephenson SL (1988) Role of endopeptidase-24.11 in the inactivation of atrial natriuretic peptide. FEBS Lett 232(l):l–8Google Scholar
  108. Kenny AJ, Stephenson SL, Turner AJ (1987) Cell surface peptidases. In: Kenny AJ, Turner AJ (eds) Mammalian ectoenzymes, Elsevier. Amsterdam, p 169Google Scholar
  109. Kerr MA, Kenny AJ (1974) The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137: 477–488PubMedGoogle Scholar
  110. Koehn JA, Norman JA, Jones BN, Le Sueur L, Sakane Y, Ghai RD (1987) Degradation of atrial natriuretic factor by kidney cortex membranes. Isolation and characterization of the primary proteolytic product. J Biol Chem 262: 11623–11627Google Scholar
  111. Kohrogi H, Nadel JA, Malfroy B, Gorman C, Bridenbaugh R, Patton JS, Borson DB (1989) Recombinant human enképhalinase (neutral endopeptidase) prevents cough induced by tachikinins in awake guinea pigs. J Clin Invest 84: 781–786PubMedGoogle Scholar
  112. Kruse TA, Bolund L, Grzeschik KH, Ropers SC (1988) Assignment of the human aminopeptidase N (peptidase E) gene to chromosome 15pl3–qter. FEBS Lett 239: 305–308Google Scholar
  113. Ksander GM, Diefenbacher CG, Yuan AM, Clark F, Sakane Y, Ghai RD (1989) Enképhalinase inhibitors 1–2,4–dibenzylglutaric acid derivatives. J Med Chem 32: 2519–2526PubMedGoogle Scholar
  114. Lebien TW, McCormack RT (1989) The common acute lymphoblastic leucemia antigen (CD10) - emancipation from a functional enigma. Blood 73(3):625–634Google Scholar
  115. Lecomte JM, Costentin J, Vlaiculescu A, Chaillet P, Marçais-Collado H, Llorens- Cortes C, Leboyer M, Schwartz JC (1986) Pharmacological properties of acetorphan, a parenterally active “enképhalinase” inhibitor. J Pharmacol Exp Ther 237: 937–944PubMedGoogle Scholar
  116. Llorens C, Schwartz JC (1981) Enképhalinase activity in rat peripheral organs. Eur J Pharmacol 69: 113–116PubMedGoogle Scholar
  117. Llorens C, Gacel G, Swerts JP, Perdrisot R, Fournié-Zaluski MC, Schwartz JC, Roques BP (1980) Rational design of enképhalinase inhibitors: substrate specificity of enképhalinase studied from inhibitory potency of various peptides. Biochem Biophys Res Commun 96: 1710–1715PubMedGoogle Scholar
  118. Llorens C, Malfroy B, Schwartz JC, Gacel G, Roques BP, Roy J, Morgat JL, Javoy- Agid F, Agid Y (1982) Enkephalin dipeptidyl carboxypeptidase (enképhalinase) activity: selective radioassay, properties and regional distribution in human brain. J Neurochem 39: 1081–1089PubMedGoogle Scholar
  119. Llorens-Cortes C, Schwartz JC (1984) Changes in turnover of cerebral monoamines following inhibition of enkephalin metabolism by thiorphan and bestatin. Eur J Pharmacol 104: 369–374PubMedGoogle Scholar
  120. Llorens-Cortes C, Gros C, Schwartz JC (1985) Study of endogenous Tyr-Gly- Gly a putative enkephalin metabolite in mouse brain: validation of a radioimmunoassay, localisation and effects of peptidase inhibitors. Eur J Pharmacol 119: 183–191PubMedGoogle Scholar
  121. Llorens-Cortes C, Gros C, Schwartz JC, Clot AM, Le Bars D (1989) Changes in levels of the tripeptide Tyr–Gly–Gly as an index of enkephalin release in the spinal cord: effects of noxious stimuli and parenterally active peptidase inhibitors. Peptides 10: 609–614PubMedGoogle Scholar
  122. Mac Lennan AJ, Maier SF (1983) Coping and the stress-induced potentiation of stimulant stereotypy in the rat. Science 219: 1091–1093Google Scholar
  123. Maldonado R, Daugé V, Callebert J, Villette JM, Fournié-Zaluski MC, Féger J, Roques BP (1989) Comparison of selective and complete inhibitors of enkephalins degrading enzymes on morphine withdrawal syndrome. Eur J Pharmacol 165: 199–207PubMedGoogle Scholar
  124. Maldonado R, Féger J, Fournié-Zaluski MC, Roques BP (1990a) Differences in physical dependence induced by selective μ or d opioid agonists and by endogenous enkephalins protected by peptidase inhibitors. Brain Res 520: 247–254PubMedGoogle Scholar
  125. Maldonado R, Daugé V, Féger J, Roques BP (1990b) Chronic blockade of D2 but not Dl–dopamine receptors facilitates behavioural responses to endogenous enkephalins, protected by kelatorphan administered in the accumbens in rats. Neuropharmacol 29: 215–223Google Scholar
  126. Malfroy B, Schwartz JC (1982) Properties of enképhalinase from rat kidney: comparison of dipeptidyl-carboxypeptidase and endopeptidase activities. Biochem Biophys Res Commun 106: 276–285PubMedGoogle Scholar
  127. Malfroy B, Swerts JP, Guyon A, Roques BP, Schwartz JC (1978) High-affinity encephalin-degrading peptidase in mouse brain and its enhanced activity following morphine. Nature 276: 523–526PubMedGoogle Scholar
  128. Malfroy B, Swerts JP, Llorens C, Schwartz JC (1979) Regional distribution of a high- affinity encephalin-degrading peptidase (enképhalinase) and effects of lesions suggest localization in the vicinity of opiate receptors in brain. Neurosci Lett 11: 329–334PubMedGoogle Scholar
  129. Malfroy B, Schofield PR, Kuang WJ, Seeburg PM, Mason AJ, Heurd WJ (1987) Molecular cloning and amino acid sequence of rat enképhalinase. Biochem Biophys Res Commun 144: 59–66PubMedGoogle Scholar
  130. Malin DH, Lake JR, Hamilton RF, Skolnick MH (1989) Augmentated analgesic effects of enképhalinase inhibitors combined with transcranial electrostimulation. Life Sci 44: 1371–1376PubMedGoogle Scholar
  131. Marcais-Collado H, Uchida G, Costentin J, Schwartz JC, Lecomte JM (1987) Naloxone reversible antidiarrheal effects of enképhalinase inhibitors. Eur J Pharmacol 144: 125–132PubMedGoogle Scholar
  132. Matsas R, Fulcher IS, Kenny AJ, Turner AJ (1983) Subtance P and Leu-enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc Natl Acad Sci USA 80: 3111–3115PubMedGoogle Scholar
  133. Matsas R, Turner AJ, Kenny A J (1984) The metabolism of neuropeptides: the hydrolysis of peptides including enkephalins, tachykinins and their analogues by endopeptidase 24.11. Biochem J 223: 433–440PubMedGoogle Scholar
  134. Matsas R, Stephenson SL, Hryszko J, Kenny AJ, Turner AJ (1985) The metabolism of neuropeptides: phase separation of synaptic membrane preparations with Triton X–114 reveals the presence of aminopeptidase N. Biochem J 231: 445–449Google Scholar
  135. Matsas R, Kenny AJ, Turner AJ (1986) An immunohistochemical study of endopeptidase 24–11 (“enképhalinase”) in the pig nervous system. Neuroscience 18: 991–1012PubMedGoogle Scholar
  136. Matthews BW (1988) Structural basis of the action of thermolysin and related zinc peptidases. Acc Chem Res 21: 333–340Google Scholar
  137. Mauborgne A, Bourgoin S, Benoleil JJ, Hirsh H, Berthier JL, Hamon M, Cesselin F (1987a) Enképhalinase is involved in the degradation of endogenous substance P released from slices of rat substantia nigra. J Pharmacol Exp Ther 243:674–680Google Scholar
  138. Mauborgne A, Lutz O, Legrand JC, Hamon M, Cesselin F (1987b) Opposite effects of δ and μ opioid receptor agonists on the in vitro release of substance P-like material from the rat spinal cord. J Neurochem 48: 529–537PubMedGoogle Scholar
  139. Meek JL, Yang HYT, Costa E (1977) Enkephalin catabolism in vitro and in vivo. Neuropharmacology 16: 151–154PubMedGoogle Scholar
  140. Meucci E, Delay-Goyet P, Roques BP, Zajac JM (1989) Binding in vivo of selective μ and d opioid agonists: opioid receptors occupancy by endogenous enkephalins. Eur J Pharmacol 171: 167–178PubMedGoogle Scholar
  141. Meynadier J, Dalmas S, Lecomte JM, Gros C, Schwartz JC (1988) Potent analgesic effects of inhibitors of enkephalin metabolism administered intrathecally to cancer patients. Pain Clinic 2: 201–206Google Scholar
  142. Morton CR, Zhao ZQ, Duggan AW (1987) Kelatorphan potentiates the effect of Met5-enkephalin in the substantia gelatinosa of the cat spinal cord. Eur J Pharmacol 140: 195–201PubMedGoogle Scholar
  143. Mumford RA, Zimmerman M, Broeke JT, Taub D, Joshua H, Rothrock JW, Hirshfield JM, Springer JP, Patchett A A (1982) Inhibition of porcine kidney “enképhalinase” by substituted N-carboxymethyl dipeptides. Biochem Biophys Res Commun 109: 1303–1309PubMedGoogle Scholar
  144. Murthy LR, Glick SD, Almenoff J, Wilk S, Orlowski M (1984) Inhibitors of an enkephalin degrading membrane bound meta loendopeptidase: analgesic properties and effects on striatal enkephalin levels. Eur J Pharmacol 102: 305–13Google Scholar
  145. Nabeshima T, Katoh A, Hiramatsu M, Kameyama T (1987) A role played by dopamine and opioid neuronal systems in stress-induced motor suppression (conditioned suppression of mobility) in mice. Brain Res 398: 354–360Google Scholar
  146. Noble F, Coric P, Soleihac JM, Turcaud S, Daugé V, Fournié-Zaluski MC, Roques BP (1990) Analgesic properties of systematically active mixed encephalin- degrading enzyme inhibitors. In: Van Ree JM, Mulder AH, Wiegant VM, Van Wimersma Greidanus TB (eds) New leads in opioid research. Excepta Medica, Amsterdam, pp 83–86Google Scholar
  147. Noble F, Soleihac JM, Lucas-Soroca E, Turcaud S, Fournié-Zaluski MC and Roques BP (1992) Inhibition of the enkephalin metabolizing enzymes by the first systemically active mixed inhibitor prodrug, RB101 induces potent analgesic responses in mice and rats. J Pharm Exp Ther 261: 181–190Google Scholar
  148. Noble F, Fournié-Zaluski MC, Roques BP (1992) Unlike morphine, the endogenous enkephalins protected by the systemically active mixed inhibitor prodrug RB101 are unable to establish a conditioned place preference in mice. Eur J Pharmacol (in press)Google Scholar
  149. Noble F, Coric P, Fournié-Zaluski MC, Roques BP (1992) Lack of physical dependence development in mice following repeated systemic administration of the mixed inhibitor prodrug of encephalin-degrading enzymes, RB101. Eur J Pharmacol (in press)Google Scholar
  150. Noble F, Turcaud S, Fournié-Zaluski MC, Roques BP (1992) Repeated systemic administration of the mixed inhibitor of encephalin-degrading enzymes, RB101, did not induce either antinociceptive tolerance or cross tolerance with morphine. Eur J Pharmacol (in press)Google Scholar
  151. Northridge DB, Jardine AG, Alabaster CT, Barclay PL, Connell JMC, Dargie HJ, Dilly SG, Findlay IN, Lever AF, Samuels GMR (1989) Effects of UK 69578: a novel atriopeptidase inhibitor. Lancet II: 591–593Google Scholar
  152. Ocain ID, Rich DM (1988) Synthesis of sulfur containing analogues of Bestatin. Inhibitors of amino peptidases by α-thiobestatin analogues. J Med Chem 31: 2193–2199Google Scholar
  153. Olsen J, Corvell GM, Konigshofer FG, Danielsen EM, Moller J, Laustsen L, Hausen OC, Welinder FG, Engberg J, Hunziber W, Spiers M, Sjostrom H, Noren (1988) Complete amino acid sequence of human intestinal amino- peptidase N as deduced from cloned cDNA. FEBS Lett 238: 307–314Google Scholar
  154. Ondetti MA, Rubin B, Cushman DW (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196: 441–444PubMedGoogle Scholar
  155. Oshita S, Yaksh TL, Chipkin R (1990) The antinociceptive effects of intrathecally administered SCH 32615, an enképhalinase inhibitor in the rat. Brain Res 515: 143–148PubMedGoogle Scholar
  156. Patey G, de la Baume S, Schwartz JC, Gros C, Fournié-Zaluski MC, Lucas-Soroca E, Roques BP (1981) Selective protection of methionine enkephaline released from brain slices by thiorphan, a potent enképhalinase inhibitors. Science 212: 1153–1155Google Scholar
  157. Pert C, Pert A, Chang JK, Fong BTW (1976) [D-Ala2]-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. Science 194:330–332PubMedGoogle Scholar
  158. Petit F, Hamon M, Fournié-Zaluski MC, Roques BP, Glowinski J (1986) Further evidence for a role of delta opiate receptors in the presynaptic regulation of newly synthesized dopamine release. Eur J Pharmacol 126: 1–9PubMedGoogle Scholar
  159. Pham I, Fournié-Zaluski MC, Corvol P, Roques BP, Michel JB (1990) Effects hypotenseur et diuretique du retrothiorphan chez le rat normal et le docasel. Arch Malad Coeur et des Vaisseaux 83: 50Google Scholar
  160. Pierart ME, Najidovski T, Appelboom TE, Deschodt-Lanckman MM (1988) Effect of human endopeptidase 24.11 (“enképhalinase”) on IL-l-induced thymocyte proliferation activity. J Immunol 140: 3808–3811PubMedGoogle Scholar
  161. Pollard M, Bouthenet ML, Moreau J, Souil E, Verroust P, Ronco P, Schwartz JC (1989) Detailed immunoautoradiographic mapping system comparison with enkephalins and SP. Neuroscience 30: 339–376PubMedGoogle Scholar
  162. Porreca F, Mosberg HI, Hurst R, Hruby VJ, Burks TF (1984) Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot–plate analgesia in the mouse. J Pharmacol Exp Ther 230: 341–348PubMedGoogle Scholar
  163. Relton JM, Gee NS, Matsas R, Turner AJ, Kenny AJ (1983) Purification of endopeptidase 24–11 (enképhalinase) from pig brain by immunoadsorbent chromatography. Biochem J 215: 519–523PubMedGoogle Scholar
  164. Rich DH (1990) Peptidase inhibitors. In: Sammes PG, Taylor JB (eds) Compre–hensive medicinal chemistry. The rational design, mechanistic study and therapeutic application of chemical compounds, vol. 2. Pergamon, Oxford, p 391Google Scholar
  165. Roderick SL, Fournié-Zaluski MC, Roques BP, Matthews BW (1989) Thiorphan and retrothiorphan display equivalent interactions when bound to crystalline thermolysin. Biochemistry 28: 1493–1497PubMedGoogle Scholar
  166. Ronco P, Pollard H, Galceran M, Delauche M, Schwartz JC, Verroust P (1988) Distribution of enképhalinase (membrane metalloendopeptidase, E.C. in rat organs. Detection using a monoclonal antibody. Lab Invest 58: 210–217Google Scholar
  167. Roques BP (1985) Inhibiteurs d’enképhalinase et exploration moléculaire des differences entre sites actifs de l’enképhalinase et de Tenzyme de conversion de Tangiotensine. J Pharmacol (Paris) 16: 5–31Google Scholar
  168. Roques BP (1988a) Novel approaches to the pharmacological modification of peptidergic neurotransmission. In: Leeming PR (ed) Proceedings of the IVth SCI-RSC medicinal chemistry symposium, topics in medicinal chemistry. Royal Society of Chemistry, Cambridge, pp 22–42Google Scholar
  169. Roques BP (1988b) Physiological role of endogenous peptide effectors studied with peptidase inhibitors. Kidney Int 34: 27–33Google Scholar
  170. Roques BP (1991) What are the relevant features of the distribution, selective binding and metabolism of opioid peptides and how can these be applied to drug design? In: Basbaum A, Besson JM (eds) Towards a new pharmacotherapy of pain. Wiley, New York, pp 257–277Google Scholar
  171. Roques BP, Beaumont A (1990) Neutral endopeptidase-24,11 inhibitors: from analgesics to antihypertensives. Trends Pharmacol Sci 11: 245–249PubMedGoogle Scholar
  172. Roques BP, Fournié-Zaluski MC (1985) A new way to antinociceptive compounds through rational design of enkephalin degrading enzyme inhibitors. In: Dalhbom R, Nilsson JLG (ed) Proceeding of international symposium on medicinal chemistry. Swedish Pharmaceutical Press, Stockholm, pp 134–146Google Scholar
  173. Roques BP, Fournié-Zaluski MC (1986) Enkephalin degrading enzyme inhibitors: a physiological way to new analgesics and psychoactive agents. In: Rapaka RS, Hawks RL (eds) Opioid peptides: molecular, pharmacology, biosynthesis and analysis. NIDA Res Monogr 70:128’–154Google Scholar
  174. Roques BP, Fournié-Zaluski MC, Soroca E, Lecomte JM, Malfroy B’, Llorens C, Schwartz JC (1980) The enképhalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature 288: 286–288PubMedGoogle Scholar
  175. Roques BP, Fournié-Zaluski MC, Florentin D, Waksman G, Sassi A, Chaillet P, Collado H, Costentin J (1982) New enképhalinase inhibitors as probes to differentiate “enképhalinase” and angiotensin-converting-enzyme active sites. Life Sci 31: 1749–1752PubMedGoogle Scholar
  176. Roques BP, Lucas-Soroca E, Chaillet P, Costentin J, Fournié-Zaluski MC (1983) Complete differentiation between “enképhalinase” and angiotensin converting enzyme inhibition by retro-thiorphan. Proc Natl Acad Sci USA 80: 3178–3182PubMedGoogle Scholar
  177. Roques BP, Daugé V, Gacel G, Fournié-Zaluski MC (1985) Selective agonists and antagonists of delta opioid receptors and inhibitors of enkephalin metabolism. Potential use in treatment of mental illness. In: Shagass C, Josiassen RC, Bridger WH, Weiss KJ, Stoff D, Simpon GM (eds) Biological psychiatry. Developments in psychiatry, vol. 7. Elsevier, New York, pp 287–289Google Scholar
  178. Roques BP, Beaumont A, Fournié-Zaluski MC (1991) Structure, localization and inhibition of endopeptidase 24.11; pharmacological studies and possible clinical applications. Pharmacol Rev (in press)Google Scholar
  179. Ruiz-Gayo M, Baamonde A, Turcaud S, Fournié-Zaluski MC, Roques BP (1992) in vivo occupation of mouse brain opioid receptors by endogenous enkephalins: blockade of enkephalin degrading enzymes by RB101 inhibits [3H]-diprenorphine binding. Brain Res 511:306–312Google Scholar
  180. Ruiz-Gayo M, Durieux C, Fournié-Zaluski MC, Roques BP (1992) Stimulation of 5 opioid receptors reduces the in vivo binding of the CCK-B selective agonist [3H]pBC264: evidence for a physiological regulation of CCKergic systems by endogenous enkephalins. J Neurochem (in press)Google Scholar
  181. Rupreht J, Ukponmwan OE, Admiral PV, Dzoljic MR (1983) Effect of phosphoramidon, a selective enképhalinase inhibitor on nociception and behaviour. Neurosci Lett 41: 331–335PubMedGoogle Scholar
  182. Sales N, Charnay Y, Zajac JM, Dubois PM, Roques BP (1989) Ontogeny of μ and δ opioid receptors and of neutral endopeptidase “enképhalinase” in human spinal cord: an autoradiographic study. J Chem Neuroanat 2: 179–188PubMedGoogle Scholar
  183. Sales N, Dutriez I, Maziere B, Ottaviani M, Roques BP (1991) Neutral endopeptidase 24.11 in rat peripheral tissues: comparative localization by “ex vivo” and “in vitro” autoradiography. Regul Pept 33: 209–222PubMedGoogle Scholar
  184. Schechter I, Berger A (1967) On the site of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27: 157–162Google Scholar
  185. Schmidt C, Peyroux J, Noble F, Fournié-Zaluski MC, Roques BP (1991) A comparison of the analgesia produced by morphine and by endogenous enkephalins (protected by mixed peptidase inhibitors) using a variety of antinociceptive tests. Eur J Pharmacol 192: 253–262PubMedGoogle Scholar
  186. Schwartz JC (1983) Metabolism of enkephalins and the inactivating neuropeptidase concept. Trends Neurosci 6: 45–48Google Scholar
  187. Schwartz JC, Malfroy B, de la Baume S (1981) Biological inactivation of enkephalins and the role of enkephalin–dipeptidyl–carboxypeptidase (“enképhalinase”) as neuropeptidase. Life Sci 29: 1715–1740Google Scholar
  188. Schwartz JC, Costentin J, Lecomte JM (1985) Pharmacology of enképhalinase inhibitors. TIPS 472–476Google Scholar
  189. Soleilhac JM, Lucas E, Beaumont A, Turcaud S, Michel JB, Crine P, Fournie- Zaluski MC, Roques BP (1992) A 94 Kdalton protein, identified as neutral endopeptidase-24.11, can inactivate atrial natriuretic peptide in the vascular endothelium. Mol Pharmacol 41: 609–614PubMedGoogle Scholar
  190. Solhonne B, Gros C, Pollard H, Schwartz JC (1987) Major localization of amino- peptidase M in rat brain microvessels. Neuroscience 22: 225–232PubMedGoogle Scholar
  191. Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A (1989) Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 248:1269–1275Google Scholar
  192. Stephenson SL, Kenny AJ (1987) The hydrolysis of α-human atrial natriuretic peptide by pig kidney microvillar membranes is initiated by endopeptidase-24.11. Biochem J 243: 183–187PubMedGoogle Scholar
  193. Stinus L, Winnock MR, Kelley AE (1985) Chronic neuroleptic treatment and mesolimbic dopamine denervation induce behavioral supersensitivity to opiates. Psychopharmacology 85: 323–328PubMedGoogle Scholar
  194. Sullivan AF, Aktf H, Barchas JD (1978) In vitro degradation of enkephalin: evidence for cleavage at the Gly–Phe bond. Psychopharmacology 2: 525–531Google Scholar
  195. Sullivan AF, Dickenson AH, Roques BP (1989) δ-Opioid mediated inhibitions of acute and prolonged noxious-evoked responses in rat dorsal horn neurones. Br J Pharmacol 98:1039–1049Google Scholar
  196. Swerts JP, Perdrisot R, Malfroy B, Schwartz JC (1979) Is “enképhalinase” identical with angiotensin converting enzyme? Eur J Pharmacol 53: 209–210PubMedGoogle Scholar
  197. Thorsett ED, Wyvratt MJ (1987) Inhibition of zinc peptidases that hydrolyse neuropeptides. In: Turner A J (ed) Neuropeptides and their peptidases. Horwood, Chichester, p 229Google Scholar
  198. Ueda H, Fukashima N, Kitao T, Ge M, Takagi H (1986) Low doses of naloxone produce analgesia in the mouse brain by blocking presynaptic autoinhibition of enkephalin release. Neurosci Lett 65: 247–252PubMedGoogle Scholar
  199. Van Amsterdam JGC, Llorens-Cortes C (1988) Inhibition of enkephalin degradation by phelorphan: effects on striatal [Met5–enkephalin levels and jump latency in mouse hot plate test. Eur J Pharmacol 154: 319–324PubMedGoogle Scholar
  200. Van Amsterdam JGC, Van Buren KJM, Blod MWH, Soujikn W (1987) Synthesis of enképhalinase B inhibitors, and their activity on isolated enkephalin–degrading enzymes. Eur J Pharmacol 135: 411–418PubMedGoogle Scholar
  201. Villanueva L, Cadden S, Chitour D, Le Bars D (1985) Failure of ES52, a highly potent enképhalinase inhibitor, to affect nociceptive transmission by rat dorsal horn convergent neurones. Brain Res 333: 156–160PubMedGoogle Scholar
  202. Vogel Z, Altstein M (1977) The adsorption of enkephalin to porous polystyrene beads: a simple assay for enkephalin hydrolysis. FEBS Lett 80: 332–336PubMedGoogle Scholar
  203. Waksman G, Hamel E, Bouboutou R, Besselievre R, Fournié-Zaluski MC, Roques BP (1984) Distribution regionale de l’enképhalinase dans le cerveau du rat par autoradiographic. C R Acad Sci [III] 299: 613–616Google Scholar
  204. Waksman G, Bouboutou R, Devin J, Bourgoin S, Cesselin F, Hamon M, Fournié- Zaluski MC, Roques BP (1985) In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain. Eur J Pharmacol 117: 233–243PubMedGoogle Scholar
  205. Waksman G, Hamel E, Fournié-Zaluski MC, Roques BP (1986) Comparative distribution of the neutral endopeptidase “enképhalinase” and mu and delta opioid receptors in rat brain by autoradiography. Proc Natl Acad Sci USA 83: 1523–1527PubMedGoogle Scholar
  206. Waksman G, Hamel E, Delay–Goyet P, Roques BP (1987) Neutral endopeptidase 24.11 mu and delta opioid receptors after selective brain lesions: an autoradiographic study. Brain Res 436: 205–216PubMedGoogle Scholar
  207. Wilcox JN, Pollard H, Moreau J, Schwartz JC, Malfroy B (1989) Localization of enképhalinase mRNA in rat brain by in situ hybridization: comparison with immunohistochemical localization of the protein. Neuropeptides 14:77–83Google Scholar
  208. Wilier JC, Roby A, Ernst M (1986) The enképhalinase inhibitor GB52, does not effect nociceptive flexion reflexes nor pain sensation in humans. Neuropharmacology 25: 819–822Google Scholar
  209. Williams JT, Macdonald JC, Christie J, North RA, Roques BP (1987) Potentiation of enkephalin action by peptidase inhibitors in rat locus coeruleus in vitro. J Pharmacol Exp Ther 243: 397–401PubMedGoogle Scholar
  210. Wood PL, Richard SW (1982) Morphine and nigrostriatal function in the rat and mouse: the role of nigral and striatal opiate receptors. Neuropharmacology 21: 1305–1310PubMedGoogle Scholar
  211. Xie J, Soleilhac JM, Renwart N, Peyroux J, Roques BP, Fournié-Zaluski MC (1989a) Inhibitors of the enkephalin degrading enzymes: modulation of the activity of hydroxamate containing compounds by modification of the C-terminal residue. Int J Pep Protein Res 34: 246–255Google Scholar
  212. Xie J, Soleilhac JM, Schmidt C, Peyroux J, Roques BP, Fournié-Zaluski MC (1989b) New kelatorphan related inhibitors of enkephalin metabolism: improved antinociceptive properties. J Med Chem 32: 1497–1503PubMedGoogle Scholar
  213. Yaksh TL, Chipkin RE (1989) Studies on the effect of SCH-34826 and thiorphan on [Met5]enkephalin levels and release in rat spinal cord. Eur J Pharmacol 167: 367–373PubMedGoogle Scholar
  214. Yaksh TL, Harty GJ (1982) Effects of thiorphan on the antinociceptive actions of intrathecal D-Ala2-Met5-enkephalin. Eur J Pharmacol 79: 293–300PubMedGoogle Scholar
  215. Yoshimura M, North RA (1983) Substantia gelatinosa neurones in vitro hyper– polarized by enkephalin. Nature 305: 529–530PubMedGoogle Scholar
  216. Zajac JM, Roques BP (1989) Properties required for reversible and irreversible radiolabeled probes for selective characterization of brain receptors and peptidases by autoradiography. In: Sharif NA, Lewis ME (eds) Brain imaging, techniques and applications. Wiley, New York, pp 18–35Google Scholar
  217. Zajac JM, Charnay Y, Soleilhac JM, Sales N, Roques BP (1987) Enkephalin- degrading enzymes and angiotensin-converting enzyme in human and rat meninges. FEBS Lett 216: 118–122PubMedGoogle Scholar
  218. Zajac JM, Lombard MC, Peschanski M, Besson JM, Roques BP (1989) Autoradiographic study of μ and δ opioid binding sites and neutral endoepeptidase 24–11 in rat after dorsal root rhizotomy. Brain Res 477: 400–403PubMedGoogle Scholar
  219. Zhang AZ, Yang HYT, Costa E (1982) Nociception, enkephalin content and dipeptidyl carboxypeptidase activity in brain of mice treated with exopeptidase inhibitors. Neuropharmacology 21: 625–630.PubMedGoogle Scholar
  220. Zuzel KA, Rose C, Schwartz JC (1985) Assessment of the role of “enképhalinase” in cholecystokinin inactivation. Neuroscience 15: 149–158PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • B. P. Roques
  • A. Beaumont
  • V. Dauge
  • M.-C. Fournié-Zaluski

There are no affiliations available

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