Derivatives of β-casomorphins with high analgesic potency

Abstract

β-Casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine β-casein with moderate opioid properties and μ-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-Pro 4 considerably increased the analgesic action and the potency on guinea-pig ileum of β-casomorphin (5) as well as of casomorphin [4] amide. The resulting D-Pro 4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe 3 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-Pro 2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro 2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro 4-substituted derivatives and D-Phe 3-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 μ-receptors.