Central nervous system effects of thyrotropin-releasing hormone and its analogues: opportunities and perspectives for drug discovery and development

Part of the Progress in Drug Research book series (PDR, volume 59)


Besides its well-known endocrine role in the thyroid system, thyrotropinreleasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide) has been long recognized as a modulatory neuropeptide. After a brief overview of the extrahypothalamic and receptor distribution, and of the neurophysiological, neuropharmacological and neurochemical effects of this tripeptide, this review discusses efforts devoted to enhance therapeutically beneficial central nervous system effects via structural modifications of the endogenous peptide. An enormous array of maladies affecting the brain and the spinal cord has been a potential target for therapeutic interventions involving agents derived from thyrotropin-releasing hormone as a molecular lead. Successful development of several centrally active analogues and recent accounts of efforts aimed at improving metabolic stability, selectivity and bioavailability are highlighted.

Key words

Thyrotropin-releasing hormone analogue mimetic prodrug central nervous system receptor pharmacology neurochemistry metabolism drug development neurological diseases. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    R. Burgus, T.F. Dunn, S. Desiderio, W. Vale and R. Guillermin: CR Acad. Sci. Hebd. Seances Acad. Sci. D269226 (1969).Google Scholar
  2. 2.
    J. Boler, F. Enzmann, K. Folkers, C.Y. Bowers and A.V. Schally: Biochem. Biophys. Res. Commun.37705 (1969).PubMedCrossRefGoogle Scholar
  3. 3.
    R. Hall, J. Amos, R. Garry and R.L. Buxton: Br. Med. J.2274 (1970).PubMedCrossRefGoogle Scholar
  4. 4.
    A.R. Harris, D. Christianson, M.S. Smith, S.L. Fang, L.E. Braverman and A.G. Vagenakis: J. Clin. Invest.61441 (1978).PubMedCrossRefGoogle Scholar
  5. 5.
    J.E. Morley: Endocr. Rev.2396 (1981).PubMedCrossRefGoogle Scholar
  6. 6.
    R.M. Lechan, P. Wu, I.M.D. Jackson, H. Wolfe, S. Cooperman, G. Mandel and R.H. Goodman: Science231159 (1986).PubMedCrossRefGoogle Scholar
  7. 7.
    E.A. Nillni and K.A. Sevarino: Endocr. Rev.20599 (1999).PubMedCrossRefGoogle Scholar
  8. 8.
    T.C. Friedman, Y.P. Loh, N.X. Cawley, N.P. Birch, S.S. Hunag, I.M.D. Jackson and E.A. Nillni: Endocrinology1364462 (1995).PubMedCrossRefGoogle Scholar
  9. 9.
    P. Schaner, R.B. Todd, N.G. Seidah and E.A. Nillni: J. Biol. Chem.27219958 (1997).PubMedCrossRefGoogle Scholar
  10. 10.
    I. Husain and S.S. Tate: FEBS Lett.152277 (1983).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Fischer and J. Spiess: Proc. Natl. Acad. Sci. USA843628 (1987).PubMedCrossRefGoogle Scholar
  12. 12.
    M.F. Scanlon and A.D. Toft, in: L.E. Braverman and R.D. Utiger (eds.): Werner and Ingbars’s The thyroid: a fundamental and clinical text, 7th Ed., Lippincott-Raven Publishers, Philadelphia 1996, 220–240.Google Scholar
  13. 13.
    A. Horita, M.A. Carino and H. Lai: Ann. Rev. Pharmacol. Toxicol.26311 (1986).CrossRefGoogle Scholar
  14. 14.
    R. Soler, F. Enzman, K. Folkers, C. Bowers and A. Schally: Biochem. Biophys. Res. Commun.37705 (1969).CrossRefGoogle Scholar
  15. 15.
    I.M.D. Jackson and S. Reichlin: Endocrinology95854 (1974).PubMedCrossRefGoogle Scholar
  16. 16.
    A. Winokur and R.D. Utiger: Science185265 (1974).PubMedCrossRefGoogle Scholar
  17. 17.
    M. Brownstein, M. Palkovits, R. Saaveda, R. Bassiry and R. Utiger: Science185267 (1974).PubMedCrossRefGoogle Scholar
  18. 18.
    I. Jackson and S. Reichlin: Endocrinology95854 (1974).PubMedCrossRefGoogle Scholar
  19. 19.
    C. Oliver, R. Eskay, N. Ben-Jonathan and J. Porter: Endocrinology95540 (1974).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Winokur and R. Utiger: Science185265 (1974).PubMedCrossRefGoogle Scholar
  21. 21.
    T. Hokfelt, K. Fuxe, O. Johansson, S. Jeffcoate and N. White: Eur. J. Pharmacol.34389 (1975).PubMedCrossRefGoogle Scholar
  22. 22.
    M. Kubek, M. Lorincz and J. Wilber: Brain Res.126196 (1977).PubMedCrossRefGoogle Scholar
  23. 23.
    N. Ogawa, Y. Yamawaki, H. Kuroda, T. Ofuji, E. Itaga and S. Kito: Brain Res.205169 (1981).PubMedCrossRefGoogle Scholar
  24. 24.
    C. Parker Jr. and A. Capdevilla: Peptides5701 (1984).PubMedCrossRefGoogle Scholar
  25. 25.
    K. Katoka, Y. Nakamura and R. Hassler: Brain Res.93309 (1973).Google Scholar
  26. 26.
    S. Manaker, A. Eichen, A. Winokur, C. Rhodes and T. Rainbow: Neurology36641 (1986).PubMedCrossRefGoogle Scholar
  27. 27.
    D. Burt and S. Snyder: Brain Res.93309 (1975).PubMedCrossRefGoogle Scholar
  28. 28.
    P.M. Hinkle: Ann. NY Acad. Sci.553176 (1989).PubMedCrossRefGoogle Scholar
  29. 29.
    M.C. Gershengorn and R. Osman: Physiol. Rev.76175 (1996).PubMedGoogle Scholar
  30. 30.
    J. Cao, D. O’Donnell, H. Vu, K. Payza, C. Pou, C. Godbout, A. Jakob, M. Pelletier, P. Lembo, S. Ahmad et al.: J. Biol. Chem.27332281 (1998).PubMedCrossRefGoogle Scholar
  31. 31.
    B.F. O’Dowd, D.K. Lee, W. Huang, T. Nguyen, R.G. Cheng, Y. Liu, B. Wang, M.C. Gershengorn and S.R. George: Mol. Endocrinol.14183 (2000).PubMedCrossRefGoogle Scholar
  32. 32.
    H. Heuer, M.K.H. Schafer, D. O’Donnell, P.K. Walker and K. Bauer: J. Comp. Neurol.428319 (2000).PubMedCrossRefGoogle Scholar
  33. 33.
    D.R. Burt and S.H. Snyder: Brain Res.93309 (1975).PubMedCrossRefGoogle Scholar
  34. 34.
    C. Prasad and R. Edwards: Brain Res.3111 (1984).PubMedCrossRefGoogle Scholar
  35. 35.
    S. Manaker, A. Winokur, W.H. Rostene and T.C. Rainbow: J. Neurosci.5167 (1985).PubMedGoogle Scholar
  36. 36.
    H. Asai, K. Kinoshita, M. Yamamura and Y. Matsuoka: Jpn. J. Pharmacol.79313 (1999).PubMedCrossRefGoogle Scholar
  37. 37.
    S. Vonhof, G.Z. Feuerstein, L.A. Cohen and V.M. Labroo: Eur. J. Pharmacol.1801 (1990).PubMedCrossRefGoogle Scholar
  38. 38.
    D.J. Ward, P.W. Finn, E.C. Griffiths and B. Robson: Int. J. Pept. Prot. Res.30263 (1987).CrossRefGoogle Scholar
  39. 39.
    A. Horita: Life Sci.621443 (1998).PubMedCrossRefGoogle Scholar
  40. 40.
    S. Harvey, V.L. Trudeau, R.J. Ashworth and S.M. Cockle: J. Endocrinol.138137 (1993).PubMedCrossRefGoogle Scholar
  41. 41.
    L. Prokai, A. Zharikova, V. Nguyen and X. Li, in: M. Lebl and R.A. Houghten (eds.): Peptides - the wave of the future, American Peptide Society, San Diego 2001, 980–981.Google Scholar
  42. 42.
    J. Hedner, T. Hedner, P. Wessberg, D. Lundberg and J. Jonason: Acta Physiol. Scand.117427 (1983).PubMedCrossRefGoogle Scholar
  43. 43.
    A.-L. Sirén, C.R. Lake and G. Feuerstein: Circ. Res.62139 (1988).PubMedCrossRefGoogle Scholar
  44. 44.
    J.E. Morley: Life Sci.251539 (1979).PubMedCrossRefGoogle Scholar
  45. 45.
    G.G. Yarbrough: Prog. Neurobiol.12291 (1979).PubMedCrossRefGoogle Scholar
  46. 46.
    G. Metcalf and P.W. Dettmar: Lancet1586 (1981).PubMedCrossRefGoogle Scholar
  47. 47.
    G. Breese, J. Cott, B. Cooper, A. Prange, M. Lippton and N. Plotnikoff: J. Pharmacol. Exp. Ther.19311 (1975).PubMedGoogle Scholar
  48. 48.
    A. Horita, M. Carino and J. Smith: Pharmacol. Biochem. Behay.5111 (1976).CrossRefGoogle Scholar
  49. 49.
    M. Miyamota, Y. Nagai, S. Norumi, Y. Saji and Y. Nagawa: Pharmacol. Biochem. Behay.17797 (1982).CrossRefGoogle Scholar
  50. 50.
    G. Kraemer, R. Mueller, G. Breese, A. Prange Jr., J. Lewis, H. Morrison and W. McKinneey Jr.: Pharmacol. Biochem. Behay.4709 (1976).CrossRefGoogle Scholar
  51. 51.
    P. Kalivas and A. Horita: J. Pharmacol. Exp. Ther.212203 (1980).PubMedGoogle Scholar
  52. 52.
    A. Horita, M. Carino and H. Lai: Fed. Proc.45795 (1986).Google Scholar
  53. 53.
    J. Cott, G. Breese, B. Cooper, I. Barlow and A. Prange: J. Pharmacol. Exp. Ther.196594 (1976).PubMedGoogle Scholar
  54. 54.
    C. Porter, V. Lotti and M. DeFelice: Life Sci.21811 (1978).CrossRefGoogle Scholar
  55. 55.
    Y. Tache, M. Lis and R. Collu: Life Sci.21841 (1977).PubMedCrossRefGoogle Scholar
  56. 56.
    H.N. Bhargava and G.A. Matwyshyn: Eur. J. Pharmacol.68147 (1980).PubMedCrossRefGoogle Scholar
  57. 57.
    P. Glue, J. Bailey, S. Wilson, A. Hudson and D.J. Nutt: Life Sci.50PL25 (1992).PubMedCrossRefGoogle Scholar
  58. 58.
    D. Schmidt: Commun. Psychopharm.1469 (1977).Google Scholar
  59. 59.
    T. Mushiroi, R. Shibahara, M. Tamura, T. Shimizu, Y. Itoh, Y. Ukai, Y. Yoshikuni and K. Kimura: Folia Pharmacol. Jpn.107237 (1996).CrossRefGoogle Scholar
  60. 60.
    A. Horita, M. Carino, J. Zabawska and H. Lai: Peptides10121 (1988).CrossRefGoogle Scholar
  61. 61.
    S.A. Kasparov and B.A. Chizh: Neuropeptides2387 (1992).PubMedCrossRefGoogle Scholar
  62. 62.
    T. Ogasawara, Y. Itoh, M. Tamura, Y. Ukai, Y. Yoshikuni and K. Kimura: Pharmacol. Biochem. Behay.53391 (1996).CrossRefGoogle Scholar
  63. 63.
    S. Molchan, A. Mellow, B. Lawlor, H. Weingartner, M. Cohen and T. Sunderland: Psy-chopharmacol.10084 (1990).Google Scholar
  64. 64.
    A.M. Mellow, T. Sunderland, R. Cohen, B. Lawlor, J. Hill, P. Newhouse, M. Cohen and D. Murphy: Psychopharmacol.98403 (1989).CrossRefGoogle Scholar
  65. 65.
    T. Lampe, J. Norris, S. Risse, E. Owens-Williams and T. Keenan, in: K. Iqbal, D.R.C. McLachlan, B. Winbald and H.M. Wishniewski (eds.): Basic mechanisms, diagnosis and therapeutic strategies, John Wiley, New York 1991, 643–648.Google Scholar
  66. 66.
    C. Peabody, T. Deblois and J. Tinkelberg: Am. J. Psychiatry143262 (1986).PubMedGoogle Scholar
  67. 67.
    T. Sunderland, A. Mellow, M. Gross, R. Cohen, P. Tariot, P. Newhouse and D. Murphy: Am. J. Psychiatry1431381 (1986).Google Scholar
  68. 68.
    A.M. Mellow, S.M. Aronson, B. Giordani and S. Berent: Biol, Psychiatry34271 (1993).CrossRefGoogle Scholar
  69. 69.
    M. Miyamoto and Y. Nagawa: Eur. J. Pharmacol.44143 (1977).PubMedCrossRefGoogle Scholar
  70. 70.
    T. Sharp, G.W. Bennett, C.A. Marsden and I.F. Tulloch: Regul. Pept.9305 (1984).PubMedCrossRefGoogle Scholar
  71. 71.
    L.R. Shian, M.H. Wu, M.T. Lin and L.T. Ho: Pharmacology30259 (1985).PubMedCrossRefGoogle Scholar
  72. 72.
    R.A. Agarwal, R.B. Rastogi and R.I. Singhal: Res. Commun. Chem. Pathol. Pharmacol.15743 (1976).PubMedGoogle Scholar
  73. 73.
    T.J. McCown and G.R. Breese: Alcohol Clin. Exp. Res.13660 (1989).CrossRefGoogle Scholar
  74. 74.
    V. Reny-Palasse, M. Constans and R. Rips: Br. J. Pharmacol.97197 (1989).PubMedCrossRefGoogle Scholar
  75. 75.
    L.B. Marangell, M.S. George, A.M. Callahan, T.A. Ketter, P.J. Pazzaglia, T.A. L’Herrou, G.S. Leverich and R.M. Post: Arch. Gen. Psychiatry54214 (1997).PubMedCrossRefGoogle Scholar
  76. 76.
    A.M. Callahan, M.A. Frye, L.B. Marangell, M.S. George, T.A. Ketter, T. L’Herrou and R.M. Post: Biol. Psychiatry41264 (1997).PubMedCrossRefGoogle Scholar
  77. 77.
    M.T. Lin, P.C. Chu and S.Y Leu: Neuroendocrinology37206 (1983).PubMedCrossRefGoogle Scholar
  78. 78.
    E. Vijayan and S.M. McCann: Endocrinology1001727 (1977).PubMedCrossRefGoogle Scholar
  79. 79.
    R.A. Vogel, B.R. Cooper, T.S. Barlow, A.J. Prange Jr., R.A. Mueller and G.R. Breese: J. Phar-macol. Exp. Ther.208161 (1979).Google Scholar
  80. 80.
    H. Ishihara, M. Mori, I. Kobayashi and S. Kobayashi: Proc. Soc. Exp. Biol. Med.178623 (1985).PubMedGoogle Scholar
  81. 81.
    Y. Tache, R.L. Stephens Jr. and T. Ishikawa: Ann. NY Acad. Sci.553269 (1989).PubMedCrossRefGoogle Scholar
  82. 82.
    M. Maeda-Hagiwara and K. Watanabe: Br. J. Pharmacol.79297 (1983).PubMedCrossRefGoogle Scholar
  83. 83.
    T.R. Lahann and A. Horita: J. Pharmacol. Exp. Ther.22266 (1982).PubMedGoogle Scholar
  84. 84.
    T. Garrick, S. Buack, A. Veiseh and Y. Tache: Life Sci.40649 (1987).PubMedCrossRefGoogle Scholar
  85. 85.
    R.B. Lynn, H.S. Feng, J. Han and F.P. Brooks: Life Sci.481247 (1991).PubMedCrossRefGoogle Scholar
  86. 86.
    Z.K. Krowicki: J. Physiol. Pharmacol.47399 (1996).PubMedGoogle Scholar
  87. 87.
    S. Amir and P.D. Butler: Peptides931 (1988).PubMedCrossRefGoogle Scholar
  88. 88.
    B. Messmer, F.G. Zimmerman and H.J. Lenz: Am. J. Physiol264G237 (1993).PubMedGoogle Scholar
  89. 89.
    J. Hedner, T. Hedner, P. Wessberg, D. Lundberg and J. Jonason: Acta Physiol. Scand.117427 (1983).PubMedCrossRefGoogle Scholar
  90. 90.
    C.B. Nemeroff, A.J. Prange Jr., G. Bissette, G.R. Breese and M.A. Lipton: Psychopharm. Commun.1305 (1975).Google Scholar
  91. 91.
    M.J. Kubek, W.C. Low, A. Sattin, S.L. Morzorati, J.L. Meyerhoff and S.H. Larsen: Ann. NY Acad. Sci.553286 (1989).CrossRefGoogle Scholar
  92. 92.
    B. Przewlocka, D. Labuz, J. Mika, A. Lipkowski, G. vanLuijtelaar, A. Coenen and W. Lason: Pol. J. Pharmacol.49373 (1997).PubMedGoogle Scholar
  93. 93.
    L.P. Renaud, H. Blume, Q. Pittman, Y. Lamour and A. Tan: Science2051275 (1979).PubMedCrossRefGoogle Scholar
  94. 94.
    M.L. Koenig, D.L. Yourick and J.L. Meyerhoff: Brain Res.730143 (1996).PubMedGoogle Scholar
  95. 95.
    T. Takeuchi, T. Takano, J. Abe, S. Takikita and M. Ohno M: Brain Develop.23662 (2001).CrossRefGoogle Scholar
  96. 96.
    S.R. White, G.K. Crane and D.A. Jackson: Ann. NY Acad. Sci.553337 (1989).PubMedCrossRefGoogle Scholar
  97. 97.
    Y. Mano, K. Matsui, E. Toyoshima and K. Ando: Acta Neurol. Scand.73352 (1986).PubMedCrossRefGoogle Scholar
  98. 98.
    K. Kinoshita, Y. Watanabe, M. Yamamura and Y. Matsuoka: Eur. J. Pharmacol.343129 (1998).PubMedCrossRefGoogle Scholar
  99. 99.
    I. Sobue, T. Takayanagi, T. Nakanishi, T. Tsubaki, M. Uono, M. Kinoshita, A. Igata, M. Miyazaki, M. Yoshida, K. Ando et al.: J. Neurol. Sci.61235 (1983).PubMedCrossRefGoogle Scholar
  100. 100.
    U. Bonucelli, A. Nuti, G. Cei, G. Rossi, L. Grasso, E. Martino and A. Muratorio: Clin. Neuropharmacol.11520 (1988).CrossRefGoogle Scholar
  101. 101.
    A.I. Faden, R. Vink and T.K. McIntosh: Ann. NY Acad. Sci.553380 (1989).PubMedCrossRefGoogle Scholar
  102. 102.
    T. Hashimoto and N. Fukuda: Eur. J. Pharmacol.20325 (1991).PubMedCrossRefGoogle Scholar
  103. 103.
    S. Manaka and K. Sano: Neurosci. Lett.8255 (1978).PubMedCrossRefGoogle Scholar
  104. 104.
    V. Askanas, W.K. Engel, K. Eagleson and G. Micaglio: Ann. NY Acad. Sci.553325 (1989).PubMedCrossRefGoogle Scholar
  105. 105.
    A. Holtz, B. Nystrom and B. Gerdin: Acta Neurol. Scand.80215 (1989).PubMedCrossRefGoogle Scholar
  106. 106.
    S.K. Salzman, E. Hirofuyi, P.B. Knight, C. Llados-Eckman, A.L. Beckman and A. Winokur: Cent. Nerv. Syst. Trauma 4, 181 (1987).PubMedGoogle Scholar
  107. 107.
    J. Shrewsbury-Gee, R.H. Lye, A. Latham and P. Slater: Exp. Brain Res.70342 (1988).PubMedCrossRefGoogle Scholar
  108. 108.
    C.T. O’Shaughnessy, N.J. Rothwell and J. Shrewsbury-Gee: Can. J. Physiol. Pharmacol.671345 (1989).PubMedCrossRefGoogle Scholar
  109. 109.
    M. Yamamoto, M. Shimizu, S. Kawabata and M. Terai: Arch. Int. Pharmacodyn. Ther.29955 (1989).PubMedGoogle Scholar
  110. 110.
    E. Cuenca, M.I. Serrano, J. Gibert-Rahola, M.S. Carrasco and J.M. Esteban: Arch. Farmacol. Toxicol.471 (1978).PubMedGoogle Scholar
  111. 111.
    G. Boschi, M. Desiles, V. Reny, R. Rips and S. Wrigglesworth: Br. J. Pharmacol.7985 (1983).PubMedCrossRefGoogle Scholar
  112. 112.
    V.A. Webster, E.C. Griffiths and P. Slater: Neurosci. Lett.4267 (1983).PubMedCrossRefGoogle Scholar
  113. 113.
    V. Reny-Palasse, J. Poncet and R. Rips: Gen. Pharmacol.18179 (1987).PubMedCrossRefGoogle Scholar
  114. 114.
    L.R. Watkins, S.N. Suberg, C.L. Thurston and E.S. Culhane: Brain Res.362308 (1986).PubMedCrossRefGoogle Scholar
  115. 115.
    S. Arancibia, F. Rage, H. Astier and L. Tapia-Arancibia: Neuroendocrinol.64257 (1996).CrossRefGoogle Scholar
  116. 116.
    G. Boschi and R. Rips: Neurosci. Lett.2393 (1981).PubMedCrossRefGoogle Scholar
  117. 117.
    A. Horita, M.A. Carino and H. Lai: Ann. Rev. Pharmacol. Toxicol.26311 (1986).CrossRefGoogle Scholar
  118. 118.
    S. Atweh, J. Simon and M. Kuhar: Life Sci.17535 (1975).CrossRefGoogle Scholar
  119. 119.
    N. Brunello and D. Cheney: J. Pharmacol. Exp. Ther.219489 (1981).PubMedGoogle Scholar
  120. 120.
    E. Santori and D. Schmidt: Reg. Peptides169 (1980).CrossRefGoogle Scholar
  121. 121.
    S. Narumi, Y. Nagai, M. Miyamoto and Y. Nagawa: Life Sci.321637 (1983).PubMedCrossRefGoogle Scholar
  122. 122.
    D. Malthe-Sorenssen, P. Wood, D. Cheney and E. Costa: J. Neurochem.31685 (1978).PubMedCrossRefGoogle Scholar
  123. 123.
    G. Yarbrough: Life Sci.33111 (1983).PubMedCrossRefGoogle Scholar
  124. 124.
    M.G. Giovannini, F. Casamenti, A. Nistri, F. Paoli and G. Pepeu: Br. J. Pharmacol.102363 (1991).PubMedCrossRefGoogle Scholar
  125. 125.
    K. Toide, M. Shinoda, M. Takase, K. Iwata and H. Yoshida: Eur. J. Pharmacol.23321 (1993).PubMedCrossRefGoogle Scholar
  126. 126.
    Y. Itoh, T. Ogasawara, T. Mushiroi, A. Yamazaki, Y. Ukai and K. Kimura: J. Pharmacol. Exp. Ther.271884 (1994).PubMedGoogle Scholar
  127. 127.
    G. Yarbrough: Nature263523 (1976).PubMedCrossRefGoogle Scholar
  128. 128.
    D. Braitman, C. Auker and D. Carpenter: Brain Res.194244 (1980).PubMedCrossRefGoogle Scholar
  129. 129.
    Q. Pittman, H. Blumen and L. Renaud: Brain Res.157364 (1978).PubMedCrossRefGoogle Scholar
  130. 130.
    A. Winokur and A. Beckman: Brain Res.150205 (1978).PubMedCrossRefGoogle Scholar
  131. 131.
    Y. Itoh, T. Ogasawara, A. Yamazaki, Y. Ukai, A. Miura and K. Kimura: J. Pharmacol. Exp. Ther.268255 (1994).PubMedGoogle Scholar
  132. 132.
    G.A. Mason, J.C. Garbutt and A.J. Prange Jr., in: F.E. Bloom and D.J. Kupfer (eds.): Psychopharmacology: the fourth generation, Raven Press, New York 1995, 493–503.Google Scholar
  133. 133.
    M.R. Kreutz, I.N. Acworth, H. Lehnert and R.J. Wurtman: Brain Res.536347 (1990).PubMedCrossRefGoogle Scholar
  134. 134.
    Y. Itoh, A. Yamazaki, Y. Ukai, Y. Yoshikuni and K. Kimura: Pharmacol. Toxicol.78421 (1996).PubMedCrossRefGoogle Scholar
  135. 135.
    S. Kasparov, H. Pawelzik and W. Zieglgänsberger: Brain Res.656229 (1994).PubMedCrossRefGoogle Scholar
  136. 136.
    T. Nakayama, T. Hashimoto, Y. Nagai: Eur. J. Pharmacol.316157 (1996).PubMedCrossRefGoogle Scholar
  137. 137.
    M. Imamura, M. Yamada, M. Mori and C. Prasad: Peptides201375 (1999).PubMedCrossRefGoogle Scholar
  138. 138.
    H. Heuer, M.K.H. Schafer and K. Bauer: Acta Med. Austriaca26119 (1999).PubMedGoogle Scholar
  139. 139.
    B.V. Zlokovic, M.B. Segal, D.J. Begley, H. Dayson and L. Rakic: Brain Res.358191 (1985).PubMedCrossRefGoogle Scholar
  140. 140.
    B.V. Zlokovie, M.N. Lipovac, D.J. Begley, H. Dayson and L. Rakie: J. Neurochem.51252 (1988).CrossRefGoogle Scholar
  141. 141.
    G. Meisenberg and W. Simmons: Life Sci.322611 (1983).PubMedCrossRefGoogle Scholar
  142. 142.
    L. Prokai: Exp. Opin. Ther. Patents7723 (1997).CrossRefGoogle Scholar
  143. 143.
    L. Prokai, in: E.M. Jucker (ed.): Progress in Drug Research, Vol. 51, Birkhäuser, Basel 1998, 95–131.CrossRefGoogle Scholar
  144. 144.
    H. Bundgaard: Design of prodrugs, Elsevier Science Publishers, Amsterdam 1985.Google Scholar
  145. 145.
    S. Muranishi, A. Sakai, K. Yamada, M. Murakami, K. Takada and Y. Kiso: Pharm. Res.8649 (1991).PubMedCrossRefGoogle Scholar
  146. 146.
    H. Bundgaard and J. Moss: Pharm. Res.7885 (1990).PubMedCrossRefGoogle Scholar
  147. 147.
    J. Moss, in: M.D. Taylor and G.L. Amidon (eds.): Peptide-based drug design, ACS Books, Washington, DC 1995, 423–471.Google Scholar
  148. 148.
    G. Metcalf: Brain Res.4389 (1982).CrossRefGoogle Scholar
  149. 149.
    R.F. Nutt, F.W. Holly, C. Homnick, R. Hirschman, D.F. Veber and B.H. Arison: J. Med. Chem.24692 (1981).PubMedCrossRefGoogle Scholar
  150. 150.
    R.J. Guiloff: Ann. NY Acad. Sci.553399 (1989).PubMedCrossRefGoogle Scholar
  151. 151.
    N.A. Sharif: Trends Pharmacol. Sci.119(1985).Google Scholar
  152. 152.
    M. Yamamura, K. Kinoshita, H. Nakagawa, T. Tanaka, K. Maeda and R. Ishida: Japan J. Pharmacol.53451 (1990).CrossRefGoogle Scholar
  153. 153.
    A.H. Rezvani, J.C. Garbutt, K. Shimoda, P.L. Garges, D.S. Janowski and G.A. Mason: Alcohol Clin. Exp. Res.16326 (1992).PubMedCrossRefGoogle Scholar
  154. 154.
    G. Mason, A. Rezvani, D.R. Grady and J.C. Garbutt: Alcohol Clin. Exp. Res.181196 (1994).PubMedCrossRefGoogle Scholar
  155. 155.
    A.H. Rezvani, J.C. Garbutt, D.H. Overstreet, L. Li, C.H. Walker, Y. Yang and G.A. Mason: Alcohol Clin. Exp. Res.21261 (1997).PubMedCrossRefGoogle Scholar
  156. 156.
    I. Fukuchi, T. Asahi, K. Kawashima, Y. Kawashima, M. Yamamura, Y. Matsuoka, K. Kinoshita: Arzneim.-Forsch./Drug Res.48353 (1998).Google Scholar
  157. 157.
    K. Kinoshita, T. Fukushima, Y. Kodama, J. Sugihara, M. Yamamura and Y. Matsuoka: Biol. Pharm. Bull.2036 (1997).PubMedCrossRefGoogle Scholar
  158. 158.
    A. Urayama, S. Yamada, K. Hirano, Y. Deguchi and R. Kimura: Life Sci.70647 (2001).PubMedCrossRefGoogle Scholar
  159. 159.
    [Anon.]: Drugs of the Future26206, (2001).Google Scholar
  160. 160.
    Y. Itoh, T. Sugimoto, Y. Ukai, A. Morino and K. Kimura: J. Pharm. Pharmacol.47833 (1995).PubMedCrossRefGoogle Scholar
  161. 161.
    Y. Ukai, T. Ogasawara, K. Ideguchi, and K. Kimura: Jpn. J. Pharmacol.46(Suppl.), 243P (1988).Google Scholar
  162. 162.
    T. Ogasawara, Y. Ukai, M. Tamura, N. Taniguchi, K. Kimura and A. Sato: Biomed. Res.14317 (1993).Google Scholar
  163. 163.
    M. Oka, Y. Itoh, Y. Ukai, Y. Yoshikuni and K. Kimura: J. Neurochem.661889 (1996).PubMedCrossRefGoogle Scholar
  164. 164.
    T. Ogasawara, Y. Nakagawa, Y. Ukai, M. Tamura and K. Kimura: Pharmacol. Biochem. Behay.51929 (1995).CrossRefGoogle Scholar
  165. 165.
    A. Khan, H. Lai, Y. Ukai and M.H. Mirolo: Pharmacol. Biochem. Behay.47477 (1994).CrossRefGoogle Scholar
  166. 166.
    T. Mushiroi, R. Shibahara, M. Tamura, T. Shimizu, Y. Itoh, Y. Ukai, Y. Yoshikuni and K. Kimura: Nippon Yakurigaku Zasshi107237 (1996).PubMedCrossRefGoogle Scholar
  167. 167.
    S. Maejima and Y. Katayama: World J. Surgery251205 (2001).CrossRefGoogle Scholar
  168. 168.
    I. Sasaki, T. Fujita, M. Murakami, A. Yamamoto, E. Nakamura, H. Imasaki and S. Muranishi: Biol. Pharm. Bull.171256 (1994).PubMedCrossRefGoogle Scholar
  169. 169.
    K. Tomiyama, S. Koide, K. Adachi, N. Koshikawa and M. Kobayashi: Neurosci. Res. Commun.223 (1998).CrossRefGoogle Scholar
  170. 170.
    Y. Miwa, N. Koshikawa, N. Miyata, Y. Koshida, M. Kobayashi and A.R. Cools: Eur. J. Pharmacol.27763 (1995).PubMedCrossRefGoogle Scholar
  171. 171.
    K. Matsui, K. Wada and S. Kwak: Eur. J. Pharmacol.254295 (1994).PubMedCrossRefGoogle Scholar
  172. 172.
    A.I. Faden: Brain Res.486228 (1989).PubMedCrossRefGoogle Scholar
  173. 173.
    T.K. McIntosh, S. Fernyak, R.L. Hayes and A.I. Faden: J. Neurotrauma10373 (1993).PubMedCrossRefGoogle Scholar
  174. 174.
    M. Miyamoto, N. Fukuda, S. Narumi, Y. Nagai, Y. Saji and Y. Nagawa: Life Sci.28861 (1981).PubMedCrossRefGoogle Scholar
  175. 175.
    M. Miyamoto, Y. Nagai, S. Narumi, Y. Saji and Y. Nagawa: Pharmacol. Biochem. Behay.17797 (1982).CrossRefGoogle Scholar
  176. 176.
    S. Narumi, Y. Nagai, M. Miyamoto and Y. Nagawa: Life Sci.321637 (1983).PubMedCrossRefGoogle Scholar
  177. 177.
    T. Nakahara, T. Matsumoto, M. Hirano, H. Uchimura, H. Yokoo, K. Nakamura, K. Ishibashi and H. Hirano: Peptides61093 (1985).PubMedCrossRefGoogle Scholar
  178. 178.
    S. Narumi, Y. Nagai, Y. Saji and Y. Nagawa: Jpn. J. Pharmacol.39425 (1985).PubMedCrossRefGoogle Scholar
  179. 179.
    Y. Nagai, S. Narumi, Y. Saji and Y. Nagawa: Folia Pharmacol. Jpn.85225 (1985).Google Scholar
  180. 180.
    Y. Nagai, S. Narumi, Y. Saji and Y. Nagawa: Folia Pharmacol. Jpn.85315 (1985).CrossRefGoogle Scholar
  181. 181.
    M. Miyamoto, N. Yamazaki, A. Nagaoka and Y. Nagawa: Ann. NY Acad. Sci. 553, 58 (1989).CrossRefGoogle Scholar
  182. 182.
    Y. Mizuki, I. Ushijima, M. Yamada, M. Tanaka and K. Inanaga: Int. Clin. Psychopharmacol.1303 (1986).PubMedCrossRefGoogle Scholar
  183. 183.
    K. Inanaga and Y. Mizuki: Int. J. Neurosci.32542 (1987).Google Scholar
  184. 184.
    S. Sakai, H. Baba, M. Sato and J.A. Wada: Epilepsia3216 (1991).PubMedCrossRefGoogle Scholar
  185. 185.
    N. Mori and T. Fukatsu: Epilepsia33994 (1992).PubMedCrossRefGoogle Scholar
  186. 186.
    R.J. Hawley, R. Kratz, R.R. Goodman, C.B. McCutchen, M. Sirdofsky and P.A. Hanson: Neurology37715 (1987).PubMedCrossRefGoogle Scholar
  187. 187.
    H.N. Bhargava and G.A. Matwyshyn: Psychopharmacology82141 (1985).CrossRefGoogle Scholar
  188. 188.
    K. Tanaka, N. Ogawa, H.H. Chou, A. Mori and N. Yanaihara: Reg. Peptides38129 (1992).CrossRefGoogle Scholar
  189. 189.
    K. Inanaga, H. Kumashiro, Y. Fukuyama, S. Ohtahara and M. Shirouzu: Epilepsia30438 (1989).PubMedCrossRefGoogle Scholar
  190. 190.
    Y. Takeuchi: CNS Drugs6341 (1996).CrossRefGoogle Scholar
  191. 191.
    J. Haruta, K. Sakumura, A. Yasuda, K. Hara, A. Saito, F. Yonemori, M. Matsusita, N. Furukawa, A. Uemure, K. Iwata et al.: 12th Symp. Med. Chem. Pharm. Soc.199152.Google Scholar
  192. 192.
    M. Matsushita, F. Yonemori, N. Furukawa, A. Ohta, K. Toide, I. Uchida and K. Iwata: Arnzeim.-Forsch./Drug Res.43813 (1993).Google Scholar
  193. 193.
    Toide K, Shinoda M, Takase M, K. Iwata and M. Yoshida: Eur. J. Pharmacol.23321 (1993).PubMedCrossRefGoogle Scholar
  194. 194.
    M. Matsusita, F. Yonemori, A. Hamada, K. Toide and K. Iwata: Eur. J. Pharmacol.276177 (1995).CrossRefGoogle Scholar
  195. 195.
    A. Urayama, S. Yamada, Y. Deguchi, Y. R. Kimura, Y. Maeda and T. Kobayashi: Life Sci.652407 (1999).PubMedCrossRefGoogle Scholar
  196. 196.
    F. Yonemori, T. Yamaguchi, H. Nakayama, K. Narita, S. Hojo and A. Tamura: J. Cereb. Blood Flow Metab.2074 (2000).PubMedCrossRefGoogle Scholar
  197. 197.
    T. Katsumata, Y. Katayama, H. Yonemori, H. Muramatsu, T. Otori, Y. Nishiyama, H. Yamada, H. Nakamura and A. Terashi: Clin. Exp. Pharm Pharmacol. Physiol.2848 (2001).CrossRefGoogle Scholar
  198. 198.
    T. Katsumata, Y. Katayama, T. Ootori, H. Muramatsu, Y. Nishiyama, H. Nakamura, T. Seta and A. Terashi: Brain Res.90162 (2001).PubMedCrossRefGoogle Scholar
  199. 199.
    N. Fukuda, O. Nashimura, M. Shikata, C. Hatanaka, M. Miyamoto, Y. Saji, R. Nakayama, M. Fujino and Y. Nagawa: Chem. Pharm. Bull.281667 (1983).CrossRefGoogle Scholar
  200. 200.
    H. Maeda, M. Suzuki, H. Sugano, M. Yamamura and R. Ishida: Chem. Pharm. Bull.36190 (1988).PubMedCrossRefGoogle Scholar
  201. 201.
    B.A. Morgan, J.D. Bower, P.W. Detmar, G. Metcalf, D.J. Schafer and B. Brown, in: E. Gross and J. Meinehofer (eds.): Peptides: structure and function, Pierce Chemical Co., Rockford 1979, 909–912.Google Scholar
  202. 202.
    D.F. Veber, F.W. Holly, S.L. Varga, R. Hirschman, V.J. Lotti, C.C. Porter and R.F. Nutt: Peptides453(1976).Google Scholar
  203. 203.
    N.A. Sharif, Z.P. To and R.L. Whiting: Neurochem. Res.1695 (1991).PubMedCrossRefGoogle Scholar
  204. 204.
    D. Brewster, P.W. Detmar and G. Metcalf: Neuropharmacology20497 (1981).PubMedCrossRefGoogle Scholar
  205. 205.
    D. Brewster, in E.C. Griffiths and G.W. Bennett (eds.): Thyrotropin-releasing hormone, Raven Press, New York 1983, 109–118.Google Scholar
  206. 206.
    C.D. Watson, M.J. Hewitt, K.C.F. Fone, S.L. Dickinson and G.W. Bennett: J. Psychopharmacol.888 (1994).PubMedCrossRefGoogle Scholar
  207. 207.
    T.M. Ballard, A.J. Hunter and G.W. Bennett: Psychopharmacology127265 (1996).PubMedGoogle Scholar
  208. 208.
    A. Goonetilleke and R.J. Guiloff: J. Neurol. Neurosurg. Psych.51201 (1995).CrossRefGoogle Scholar
  209. 209.
    P. Holzer: Drug News Perspect.12463 (1999).CrossRefGoogle Scholar
  210. 210.
    A. Kiraly, G. Suto, B. Tam, V. Hermann and G. Mozsik: J. Physiol. (Paris)94131 (2000).CrossRefGoogle Scholar
  211. 211.
    S.B. Deshpande and J.E. Warnick: Eur. J. Pharmacol.271439 (1994).PubMedCrossRefGoogle Scholar
  212. 212.
    S. Vickers, C.A.H. Duncan, B.H. Arison, H.G. Ramjit, A Rosegay, R.F. Nutt and D.F. Veber: Drug. Metab. Dispos.11147 (1983).PubMedGoogle Scholar
  213. 213.
    L. Lankiewicz, C.Y. Bowers, G.A. Reynolds, V. Labroo, L.A. Cohen, S. Vonhof, A.-L. Sirén and A.F. Spatola: Biochem. Biophys. Res. Commun.184359 (1992).PubMedCrossRefGoogle Scholar
  214. 214.
    T. Szirtes, L. Kisfaludy, E. Palosi and L. Szporny: J. Med. Chem.27741 (1984).PubMedCrossRefGoogle Scholar
  215. 215.
    A.E. Pekary and A. Sattin: Peptides221161 (2001).PubMedCrossRefGoogle Scholar
  216. 216.
    A. Sarkadi, S. Szabo, J. Laszy, A. Ambrus and L. Szporny: Arzneim.-Forsch./Drug Res.381134 (1988).Google Scholar
  217. 217.
    M. Oka, Y. Ochi, K. Furukawa, T. Ito, Y. Miura, T. Karasawa and K. Kadokawa: Arzneim.- Forsch./Drug Res.39297 (1989).Google Scholar
  218. 218.
    M. Oka, T. Ito, K. Furukawa, T. Karasawa and T. Kadokawa: Arch. Int. Pharmacodyn. Ther.30618 (1990).PubMedGoogle Scholar
  219. 219.
    G. Benzi, A. Gorini, R. Arnaboldi, B. Ghigini and R.F. Villa: Neurobiol. Aging15409 (1994).PubMedCrossRefGoogle Scholar
  220. 220.
    Y. Noda, K. Furukawa, H. Kohayakawa and M. Oka: Pharmacol. Biochem. Behay.52695 (1995).CrossRefGoogle Scholar
  221. 221.
    E Drago, G. Coppi, P.A. Antonuzzo, C. Valerio, A.A. Genazzani, M. Grassi, R. Raffaele and U. Scapagnini: Neurobiol. Aging1767 (1996).PubMedCrossRefGoogle Scholar
  222. 222.
    I. Panocka, G. Coppi, A. Maggioni, V. Olgiati, M. Sabbatini and E Amenta: Drug Exp. Clin. Res.2313 (1997).Google Scholar
  223. 223.
    M. Sabbatini, G. Coppi, A. Maggioni, V. Olgiati, I. Panocka and E Amenta: Mech. Ageing Dev.104183 (1998).PubMedCrossRefGoogle Scholar
  224. 224.
    E Amenta, M. Sabbatini, G. Coppi, A. Maggioni, V. Olgiati and I. Panocka: Drug Exp. Clin. Res.2377 (1997).Google Scholar
  225. 225.
    M. Bodo, G. Perjes, E. Kalman, E. Bacskai, K. Berko, A. Sarkadi, I. Nagy, K.L. Keim, F.M. Matysik, K. Csomor et al.: Pharmacol. Res.45419 (2001).CrossRefGoogle Scholar
  226. 226.
    L. Parnetti, L. Ambrosoli, G. Abate, C. Azzini, R. Balestreri, L. Bartorelli, A. Bordin, G. Crepaldi, G. Cristianini, D. Cucinotta et al.: Acta Neurol. Scand.92135 (1995).PubMedCrossRefGoogle Scholar
  227. 227.
    G. Gasbarrini, G. Stefanini, G. Addolorato, F. Foschi, C. Ricci, P. Bertolotti, G. Voltolini, E. Bonavita, R. Bertoncelli, G. Renzi et al.: Arch. Gerontol. Geriat.2633 (1997).CrossRefGoogle Scholar
  228. 228.
    L. Parnetti, L. Ambrosoli, G. Agliati, P. Caratozzolo, L. Fossati, L. Frattola, N. Martucci, L. Murri, G. Nappi, F.M. Puca et al.: Acta Neurol. Scand.93456 (1996).PubMedCrossRefGoogle Scholar
  229. 229.
    E. Ferrari, D. Cucinotta, M.G. Albizatti, L. Bartorelli, N. Colombo, G. Ferretti, G. Galetti, U. Galliano, L.G. Grezzana, V. Pedone et al.: Arch. Gerontol. Geriat.163(Suppl.), 6 (1998).Google Scholar
  230. 230.
    G. Reboldi, L. Parnetti, F. Santeusanio, L. Ambrosoli, B. Palumbo, A. Cherubini, R. Girardello, A. Poli, D.T. Lowenthal and U. Senin: J. Clin. Pharmacol.36823 (1996).PubMedGoogle Scholar
  231. 231.
    A.I. Faden, G.B. Fox, L. Fan, G.L. Araldi, L. Qiao, S. Wang and A.P. Kozikowski: Am. J. Physiol.277(Regulatory Integrative Comp Physiol), R1196 (1999).PubMedGoogle Scholar
  232. 232.
    L. Flohé, K. Bauer, E. Friedrichs, W.A. Günzler, H.H. Hennies, S. Herring, E Lagler, F. Ötting and E. Schwertner, in: E. Griffiths and G.W. Bennett (eds.): Thyrotropin-releasing hormone, Raven Press, New York 1983, 327–340.Google Scholar
  233. 233.
    L. Prokai, K. Prokai-Tatrai and N. Bodor: Med. Res. Rev.20367 (2000).PubMedCrossRefGoogle Scholar
  234. 234.
    L. Prokai, X. Ouyang, W.-M. Wu and N. Bodor: J. Am. Chem. Soc.1162643 (1994).CrossRefGoogle Scholar
  235. 235.
    L. Prokai, K. Prokai-Tatrai, X. Ouyang, H.-S. Kim; W.-M. Wu, A. Zharikova and N. Bodor: J. Med. Chem.424563 (1999).PubMedCrossRefGoogle Scholar
  236. 236.
    L. Prokai, X. Ouyang, K. Prokai-Tatrai, J. Simpkins and N. Bodor: Eur. J. Med. Chem.33879 (1998).CrossRefGoogle Scholar
  237. 237.
    L. Prokai, K. Prokai-Tatrai, W.-M. Wu, J. Wu, X. Ouyang, H.-S. Kim, A. Zharikova, J. Simpkins and N. Bodor, in: J.P. Tam and P.T.P. Kaumaya (eds.): Peptides - frontiers of peptide science, Kluwer Academic Publishers, Dordrecht 1998, 834–836.Google Scholar
  238. 238.
    S.-H. Yoon, J. Wu, W.-M. Wu, L. Prokai and N. Bodor: Bioorg. Med. Chem.81059 (2000).PubMedCrossRefGoogle Scholar
  239. 239.
    K. Prokai-Tatrai, P. Perjesi, A. Zharikova, X. Li and L. Prokai: Bioorg. Med. Chem. press. Google Scholar
  240. 240.
    A.A. Mazurov, S.A. Andronati, T.I. Korotenko, N.I. Sokolenko, A.I. Dyadenko, Y.E. Shapiro, V.Y. Gorbatyuk and T.A. Voronina: Bioorg. Med. Chem. Lett.62595 (1996).CrossRefGoogle Scholar
  241. 241.
    F.H.C. Crick: J. Mol. Biol.19548 (1966).PubMedCrossRefGoogle Scholar
  242. 242.
    A.A. Mazurov, S.A. Andronati, T.I. Korotenko, N.I. Sokolenko, A.I. Dyadenko, Y.E. Shapiro, V.Y. Gorbatyuk and T.A. Voronina: Bioorg. Med. Chem.52029 (1997).PubMedCrossRefGoogle Scholar
  243. 243.
    G.L. Olson, H.-C. Cheung, E. Chiang, V.S. Madison, J. Sepinwall, G.P. Vincent, A. Winokur and K.A. Gary: J. Med. Chem.382866 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  1. 1.Center for Drug Discovery, College of Pharmacy and the McKnight Brain InstituteUniversity of Florida Health Science CenterGainesvilleUSA

Personalised recommendations