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 language | English |
|---|---|
| Pages (from-to) | 216-226 |
| Number of pages | 11 |
| Journal | Chemical Biology and Drug Design |
| Volume | 70 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2007 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
Cite this
N-terminal bis-(2-chloroethyl)amino and fluorosulphonyl analogues of calcitonin gene-related peptide(8-37) : Irreversible antagonists at calcitonin gene-related peptide receptors. / Taylor, Christopher K.; Abel, Peter W.; Hulce, Martin; Smith, D. David.
In: Chemical Biology and Drug Design, Vol. 70, No. 3, 09.2007, p. 216-226.Research output: Contribution to journal › Article
}
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=34548169355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548169355&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2007.00558.x
DO - 10.1111/j.1747-0285.2007.00558.x
M3 - Article
C2 - 17718716
AN - SCOPUS:34548169355
VL - 70
SP - 216
EP - 226
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
SN - 1747-0277
IS - 3
ER -