Effect of Phe-D-Met-Arg-Phe-NH2 and other Phe-Met-Arg-Phe-NH2-related peptides on mouse colonic propulsive motility: a structure-activity relationship study

RB Raffa and HI Jacoby

Department of Biological Research, R. W. Johnson Pharmaceutical Research Institute, McNeil Pharmaceutical, Spring House, Pennsylvania.

The effect of several i.c.v.-administered FMRFamide (Phe-Met-Arg-Phe- NH2)-like peptides (FaRPs) on mouse colonic propulsive motility was examined. Dose-related inhibition of propulsive motility (measured as an increase in the time of colonic bead expulsion) was produced by analogs with either the sequence (-)F[X]RFamide or with the FMRFamide sequence containing D-amino acid substitutions. The C-terminal dipeptide sequence Arg-Phe-NH2 was sufficient to produce this effect. D- amino acid substitution in the second position, i.e., [D-Met2]- FMRFamide (DMFa), conferred significantly enhanced activity (nearly maximal obtainable response under the test conditions) in this preparation (ED25 = 2.3 micrograms = 3.8 nmol). DMFa did not block the action of morphine but, like morphine, was blocked by the opioid antagonist naloxone and was attenuated by 24-hr pretreatment with the selective mu-1 opioid antagonist naloxonazine (35 mg/kg s.c.). It is concluded that a variety of FaRPs, particularly those with a nonpolar residue in the first position and with Arg in the third position, behave as opioid-like agonists, not antagonists, on mouse colonic propulsive motility. DMFa is identified as the most active FaRP studied to date on this endpoint.

Volume 254, Issue 3, pp. 809-814, 09/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics