Structure-function relationships in gastrin-like peptides

Abstract

As the work leading to the elucidation of the structures of the hog gastrins was nearing completion and the synthesis of the hormones was being planned, it became clear that the glycine residue at position 13 offered a convenient dividing point in the synthesis. Our colleagues at Liverpool subsequently became concerned with the synthesis of 1-13 fragments and we with the synthesis of the 14-17 fragment, Try-Met-Asp-Phe-NH 2 , of the molecules. Not long afterwards the tetrapeptide amide had been synthesised and found by Tracy & Gregory (1964) to possess all the physiological properties of the natural hormones. The finding of activity in so small a ‘stump’ of the molecule offered scope for an investigation of structure-function relationships on a scale not hitherto possible with polypeptide hormones. We attached value to such an investigation on two accounts. First, the results might contribute towards our knowledge of the mode of action of the gastrins and polypeptide hormones in general. Secondly, conclusions enabling a more rational approach to the design of inhibitors of the action of polypeptide hormones might be provided. Both expectations were clearly pertinent to an objective of our researches—the development of therapeutic agents of value in the assessment and control of gastric secretory function in humans. For the purposes of the investigation we prepared about 500 derivatives or analogues of the tetrapeptide amide comprising: ( a ) various N -terminally acylated derivatives of the tetrapeptide amide, ranging from simple derivatives like the acetyl (Ac-Try-Met-Asp-Phe-NH 2 ) to extended peptides like the hexadecapeptide amide sequence (2-17) of human gastrin (H-Gly-Pro-Try-Leu-(Glu) 5 -Ala-Tyr-Gly-Try-Met-Asp-Phe-NH 2 ), ( b )analogues derived by single replacements at the five main positions in the tetrapeptide amide (the four amino-acid and the terminal amide positions), and ( c ) analogues derived by two or more replacements at the five positions. The tripeptide amide, H-Met-Asp-Phe-NH 2 , dipeptide amide, H-Asp-Phe-NH 2 , and various analogues of these compounds were also prepared and examined, but since in general these were devoid of biological activity they will not be discussed. Thirty-three derivatives or analogues of the tetrapeptide amide were selected and examined in the conscious dog in the Physiological Laboratory, University of Liverpool; the results describing their influence on gastric acid secretion, gastric motility, intestinal motility, pancreatic secretion, gastric motility, intestinal motility, pancreatic secretion, and pepsin secretion have been reported (Morley, Tracy & Gregory 1965). The present paper concerns results obtained in rats in our own laboratories with a larger group of the compounds in respect of acid-stimulatory properties only.