Synthesis and Opioid Activity of [Sar4]Dermorphin-Tetrapeptide Analogues

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Abstract
The modification of the dermorphin-(1-4)-tetrapeptide structure led to analog with potent opioid activity in vitro and in vivo. [Sar4]Tetrapeptides such as H2N-CH(NH)-Tyr-D-Ala-Phe-Sar-D-NH-CH(CH3)C6H5 (VII) whose terminal amino group is replaced by the guanidino function and whose C-terminus is amidated by (R)-(+)-.alpha.-methylbenzylamine, show peripheral and central opioid activities comparable to or higher than those of dermorphin. The potency of VII in the different tests was as follows: guinea pig ileum (GPI) IC50 [median inhibitory concentration] = 0.09 nM, mouse vas deferens (MVD) IC50 = 0.69 nM, tail-flick ED50 = 8.91 pmol/mouse, i.c.v. [intracerebroventricular] and 4.54 .mu.mol/kg, s.c. This dermorphin-(1-4)-tetrapeptide derivative is .apprx. 650 and 950 times as active as morphine in the 2 in vitro tests, respectively. The MVD/GPI potency ratio of the new peptides suggests a .mu.-type agonist behavior.