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.
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.
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Department of Biological Research, R. W. Johnson Pharmaceutical Research Institute, McNeil Pharmaceutical, Spring House, Pennsylvania.
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D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D019835:FMRFamide; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009479:Neuropeptides; D018377:Neurotransmitter Agents; D019835:FMRFamide; D009020:Morphine