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N‐terminal bis‐(2‐Chloroethyl)amino and Fluorosulphonyl Analogues of Calcitonin Gene‐Related Peptide(8‐37): Irreversible Antagonists at Calcitonin Gene‐Related Peptide Receptors
Author(s) -
Taylor Christopher K.,
Abel Peter W.,
Hulce Martin,
Smith D. David
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00558.x
Subject(s) - calcitonin gene related peptide , calcitonin , peptide , calcitonin receptor , receptor , amino terminal , chemistry , gene , peptide sequence , biochemistry , endocrinology , biology , neuropeptide
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 μ m and 1.5 μ m 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‐His 10 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 .