Derivatives of beta-casomorphins with high analgesic potency.
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.
D000595:Amino Acid Sequence; D000700:Analgesics; D000818:Animals; D002364:Caseins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000008:administration & dosage / Q000494:pharmacology*; D006207:Half-Life; D007276:Injections, Intraventricular; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000700:Analgesics; D002364:Caseins; D004723:Endorphins; D009271:Naltrexone; C021968:beta-casomorphins