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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

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.