N-terminal bis-(2-chloroethyl)amino and fluorosulphonyl analogues of calcitonin gene-related peptide(8-37): Irreversible antagonists at calcitonin gene-related peptide receptors

Christopher K. Taylor, Peter W. Abel, Martin Hulce, D. David Smith

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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-α-benzoyl-h-α-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 μm and 1.5 μm 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.

Original languageEnglish
Pages (from-to)216-226
Number of pages11
JournalChemical Biology and Drug Design
Volume70
Issue number3
DOIs
StatePublished - Sep 2007

Fingerprint

Calcitonin Gene-Related Peptide Receptors
Calcitonin Gene-Related Peptide
Structure-Activity Relationship
Thoracic Aorta
Washing
Aorta
Assays
calcitonin gene-related peptide (8-37)
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

Cite this

@article{e0e857f5fde04345ad10808c0984a85b,
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-α-benzoyl-h-α-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 μm and 1.5 μm 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.",
author = "Taylor, {Christopher K.} and Abel, {Peter W.} and Martin Hulce and Smith, {D. David}",
year = "2007",
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T1 - N-terminal bis-(2-chloroethyl)amino and fluorosulphonyl analogues of calcitonin gene-related peptide(8-37)

T2 - Irreversible antagonists at calcitonin gene-related peptide receptors

AU - Taylor, Christopher K.

AU - Abel, Peter W.

AU - Hulce, Martin

AU - Smith, D. David

PY - 2007/9

Y1 - 2007/9

N2 - 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-α-benzoyl-h-α-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 μm and 1.5 μm 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.

AB - 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-α-benzoyl-h-α-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 μm and 1.5 μm 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.

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