Structure-activity relationships for Periplaneta americana hypertrehalosemic hormone I: The importance of side chains and termini

Abstract

Single amino acid replacement analogues for the native hypertrehalosemic hormone I of the American cockroach, Periplaneta americana (Pea-CAH-I: pGlu-Val-Asn-Phe-Ser-Pro-Asn-Trp-NH2), have been prepared by solid-phase peptide synthesis, and complete dose-response curves have been measured in P. americana monitoring the carbohydrate-mobilizing activity in vivo. All analogues that elicited hypertrehalosemia showed similar time-response courses, indicating that transport and degradation rates were comparable. Comparison of the potency and efficacy parameters of the analogues under study in the dose-response curves revealed four activity groups: 1) analogues that had the aromatic amino acids at positions 4 (phenylalanine) or 8 (tryptophan) replaced by alanine and glycine, respectively, had trace activity; 2) analogues with alanine at positions 1 or 2 had low potencies and an apparent biphasic dose-response relationship without much observable loss of efficacy; 3) analogues with glycine at positions 6 and 7 had potencies and efficacies most similar to Pea-CAH-I; and 4) analogues that had either an alanine instead of asparagine residue at position 3, or had a substitution of the carboxylamide function at the C-terminus by a carboxyl function reached apparent saturation, but only achieved 50-57% of the maximum activity of the native peptide. The potency profile for the analogue set is consistent with the importance of the N-terminal pentapeptide and the C-terminal tryptophan interacting with receptor(s) more closely than the side chains at positions 6 and 7, which are predicted to be the corner residues of a beta-turn. Finally, the biphasic dose-response curves observed for more than one analogue suggest the potential that receptors for Pea-CAH-I exist in more than one form.