Synthesis and Biological Activity of C-Terminally Truncated Fragments of Human α-Calcitonin Gene-Related Peptide

D. David Smith, Jianzhong Li, Qiming Wang, Richard F. Murphy, Thomas E. Adrian, Yvonne Elias, Charles S. Bockman, Peter W. Abel

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C-terminally truncated fragments of human α-calcitonin gene-related peptide (h-α-CGRP) were tested for their ability to stimulate amylase secretion from pancreatic acinar cells and relax precontracted mesenteric arteries. h-α-CGRP, h-α-CGRP (1-36), h-α-CGRP (1-35), and h-α-CGRP (1- 34) were made by Merrifield's solid-phase peptide synthesis methodology. Peptides were purified by gel filtration, cation-exchange chromatography, and semipreparative reversed-phase high-performance liquid chromatography. The products were characterized by amino acid analysis, mass spectrometry, and tryptic digestion. h-α-CGRP stimulated amylase secretion from dispersed guinea pig pancreatic acini in a biphasic concentration-dependent manner. The initial increase in amylase secretion reached 8% of total cellular amylase content with an ED50 value of 7.7 nM, and the second increase reached 11% of total cellular amylase content at a concentration of h-α-CGRP of 10-4 M. h-α-CGRP (1-36) caused a small, significant increase in amylase release. C-terminally truncated fragments h-α-CGRP (1-35) and h-α-CGRP (1-34) did not increase amylase release at concentrations -5 M. At concentrations >10-5 M the fragments h-α-CGRP (1-35) and h-α-CGRP (1-34) caused a smaller increase in amylase release than that caused by h-α-CGRP whereas h- α-CGRP (1-36) caused the same increase. h-α-CGRP caused a concentration- dependent relaxation of rat mesenteric artery, precontracted with prostaglandin F(2α), with an EC50 of 2.9 nM and a maximal relaxation that was 60% of the prostaglandin F(2α)-induced tone. h-α-CGRP (1-35) also relaxed the mesenteric artery in a concentration-dependent manner with a maximum response that was 40% of the prostaglandin F(2α)-induced tone. The remaining fragments did not relax rat mesenteric arteries. Additionally, h- α-CGRP (1-36) and h-α-CGRP (1-34) did not block h-α-CGRP-induced relaxation of the mesenteric artery. An intact C-terminus is required for h- α-CGRP to cause potent biological effects in pancreatic acini and mesenteric artery. The different effects of h-α-CGRP (1-35) in mesenteric artery compared with those in pancreatic acini suggest that the CGRP receptors in these two tissues may be different.

Original languageEnglish (US)
Pages (from-to)2536-2541
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - 1993

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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