Structure-Activity Relationships for the Lipid-Mobilising Action of Locust Adipokinetic Hormone. Synthesis and Activity of a Series of Hormone Analogues

Abstract

A series of compounds structurally related to adipokinetic hormone, the decapeptide neurohormone < Glu-Leu-Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH2, were prepared by synthesis and by enzymic cleavages of synthetic hormone. Their relative agonist activities in mobilizing lipids over a fixed time interval (1 h) in locusts [Schistocerca gregaria, Locusta migratoria] were assessed. The similar time courses for lipid release shown by 2 of the peptide analogues and adipokinetic hormone suggested that the analogues and the hormone were transported to the receptors on the fat body cells, and were degraded at similar rates. The analogue activities could be correlated with the structural requirements of the locust fat body hormone receptors. The requirements for activity were demonstrated. Residues 1-8 from the N-terminus were necessary to elicit some activity (20%). Residues 5 and 7 in the octapeptide could be changed without affecting activity but L-pyroglutamic acid as the N-terminal residue was necessary for maximum activity both in the octapeptide and the decapeptide. Full activity was achieved only by adding the dipeptide glycyl threonine amide to the active octapeptide core. In the decapeptide, residues could not be interchanged to the same extent as in the octapeptide without reducing activity. The peptide probably has to be uncharged. Inactive analogues of 7 residues or less did not interfere in the hormone-receptor interaction.