PSEUDODIPEPTIDE ANALOGS OF THE PYROKININ/PBAN (FXPRLA) INSECT NEUROPEPTIDE FAMILY CONTAINING CARBOCYCLIC PRO-MIMETIC CONFORMATIONAL COMPONENTS

Three N-terminal amino acid residues of the C-terminal core pentapeptide Phe-X-Pro-Arg-Leu-NH2 (X = Gly, Ser, Thr, Val) of the pryokinin/PBAN insect neuropeptide family were replaced by nonpeptide moieties. To reestablish some of the conformational properties lost upon removal of the peptide bonds and Pro of the three amino acid residue block, carbocyclic Pro-mimetic components were incorporated into pseudodipeptide analogs. The most active analog contained a trans-DL-1,2-cyclopentanedicarboxyl carbocyclic component and proved to be over 3 orders of magnitude more potent than a simple, straight chain pseudodipeptide analog and approached the potency of the pentapeptide core in a cockroach hindgut myotropic bioassay. The pseudodipeptide analog retains a critical carbonyl residue which can participate in a hydrogen bond that stabilizes a beta-turn conformation in the active core region of the pyrokinin/PBAN peptides. This study demonstrates that knowledge of active conformation can be used to enhance the biological potency of pseudopeptide mimetic analogs of insect neuropeptides. The analogs represent a milestone in the development of pseudopeptide and nonpeptide mimetic analogs of this peptide family, which has been associated with such critical physiological processes as hindgut and oviduct contraction, pheromone biosynthesis, diapause induction, and induction of melanization and reddish coloration in a variety of insects. Mimetic analogs are potentially valuable tools to insect neuroendocrinologists studying these physiological processes and/or engaged in the development of future pest management strategies.