ACYL, PSEUDOTETRAPEPTIDE, TRIPEPTIDE AND DIPEPTIDE ACTIVE-CORE ANALOGS OF INSECT NEUROPEPTIDES

Pseudopeptides of the achetakinin insect neuropeptide family were synt hesized by replacing the amino acid blocks Phe-, Phe-Tyr-, and Phe-Tyr -Pro- of the active-core pentapeptide Phe-Tyr-Pro-Trp-Gly-NH2 with hyd rocinnamic acid, 6-phenylhexanoic acid, and both 9-phenylnonanoic and 6-phenylhexanoic acid, respectively. All four of these analogs retaine d myotropic activity, demonstrating that the active core could be redu ced from a pentapeptide to a modified dipeptide. Most notable of these was the pseudotetrapeptide hydrocinnamyl-Tyr-Pro-Trp-Gly-NH2, which r etained 70% of the potency and over 85% of the maximal activity of the parent pentapeptide. The N-terminal amino group, the phenol ring of t he Tyr residue, the sulfate moiety and the Gly residue of the insect s ulfakinin active core Tyr(SO3H)-Gly-His-Met-Arg-Phe-NH2 were all repla ced by dodecanedioic acid. The resulting pseudotetrapeptide, dodecandi oyl-His-Nle-Arg-Phe-NH2, elicited myostimulatory activity. Conversely, the related acyl pseudopentapeptide azelayl-Gly-His-Nle-Arg-Phe-NH2 p roved myoinhibitory. A possible explanation for these disparate biolog ical responses is discussed. These acyl pseudopeptides are important a dvances towards the eventual development of stable, potent mimetic ago nists and antagonists of insect neuropeptides. (C) Munksgaard 1993.