Phe1-substituted beta-casomorphin-5 analogues with analgesic activity

The antinociceptive potency of linear and cyclic beta-casomorphin-5 (CM-5) analogues, modified in position 1 by substitution of the tyrosine (Tyr) by the phenylalanine (Phe) residue, was studied using the vocalization test. With the exception of the linear [Phe1,D-Orn2]CM-5, the Phe1-substituted linear and cyclic casomorphin analogues exhibit remarkable analgesic potency compared to morphine, although the opioid receptor affinity and the opioid activity in vitro is diminished compared to the corresponding Tyr-containing analogues. The analgesic effect of the compounds is mediated by activation of opioid receptors, because it can be antagonized with naloxone. Furthermore, it was demonstrated that the [Phe1,D-Orn2,D-Pro4]CM-5, which was about sixfold more potent than morphine, developed cross-tolerance to morphine.