title: N-terminal bis-(2-chloroethyl)amino and fluorosulphonyl analogues of calcitonin gene-related peptide(8-37): irreversible antagonists at calcitonin gene-related peptide receptors.
abstract: Synthesis of the first irreversible calcitonin gene-related peptide receptor antagonists is described. bis-(2-chloroethyl)amino and fluorosulphonyl groups were incorporated into the 4-position of the N-terminal benzoyl group of a potent competitive antagonist, N-alpha-benzoyl-h-alpha-CGRP(8-37) (analogues 4 and 6). Based on previous structure-activity relationships, a second pair of N-terminally modified analogues was synthesized containing a novel benzylated-His residue in position 10 (analogues 5 and 7). In separate experiments, SK-N-MC cells and mouse thoracic aortas were bathed in solutions containing 5 microM and 1.5 microM of each analogue, respectively. After extensive washing, calcitonin gene-related peptide concentration-response curves were generated for cAMP production in SK-N-MC cells and relaxation of mouse aortas. All analogues caused >20% reductions in maximal calcitonin gene-related peptide efficacy in both assays with analogue 5 containing an N-terminal bis-(2-chloroethyl)amino-benzoyl group and a benzylated-His10 residue completely abolishing cAMP production in SK-N-MC cells. Reductions in maximal responses were dependent on the analogue concentration. Analogue 4 also caused more than 10-fold reductions in the potency of the calcitonin gene-related peptide-mediated effects, whereas analogues 5, 6 and 7 have no significant effect on calcitonin gene-related peptide potency. These data indicate that all analogues bind irreversibly to calcitonin gene-related peptide receptors. The bis-(2-chloroethyl)amino-modified analogues 4 and 5 were more effective than the fluorosulphonyl-modified analogues 6 and 7.
authors: Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178-0405, USA.
authors: Christopher K
authors: CK
authors: Taylor
authors: Peter W
authors: PW
authors: Abel
authors: Martin
authors: M
authors: Hulce
authors: D David
authors: DD
authors: Smith
mesh_terms: D000586:Amination; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives* / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002713:Chlorine / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D013455:Sulfur / Q000737:chemistry*
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018015:Receptors, Calcitonin Gene-Related Peptide; D005461:Fluorine; D002713:Chlorine; D013455:Sulfur; D015740:Calcitonin Gene-Related Peptide