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Derivatives of beta-casomorphins with high analgesic potency
Authors:H Matthies  H Stark  B Hartrodt  H L Ruethrich  H T Spieler  A Barth  K Neubert
Institution:Institut für Neurobiologie und Hirnforschung der Akademie der Wissenschaften der DDR DDR-3090 Magdeburg German Democratic Republic Leipziger Strasse 44;Institut für Pharmakologie und Toxikologie, Medizinische Akademie Magdeburg German Democratic Republic;Sektion Biowissenschaften der Martin-Luther-Universität, Halle German Democratic Republic
Abstract:Beta-casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine beta-casein with moderate opioid properties and mu-receptor affinity, was modified by substituting for the natural L-amino acids their D-analogs, and D-pipecolic acid, as well as by amidation of the C-terminal. Substitution of D-Pro or D-pipecolic acid for L-Pro4 considerably increased the analgesic action and the potency on guinea-pig ileum of beta-casomorphin (5) as well as of casomorphin 4] amide. The resulting D-Pro4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe3 enhanced, even though to a lesser degree, the antinociceptive action. Both naltrexone and naloxone completely blocked the effects in vivo and in vitro. The substitution of D-Pro for L-Pro2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro4-substituted derivatives and D-Phe3-CM(5) from the other modified casomorphins and morphine, indicating that the analgesic potency of the former was about ten times that of the latter group in the case of identical GPI-potency. This may involve different subpopulations of opiate mu-receptors.
Keywords:β-Casomorphin  Analgesic action  μ-Receptors  Isoreceptors  Deprolorphin  Deproceptin
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