CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.
Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action. Methods CGRP stimulation of four intracellular signalling molecules relevant to pain (cAMP, CREB, p38 and ERK) were examined in rat TG neurons and compared to transfected CGRP and AMY1 receptors in Cos7 cells. Results In TG neurons, olcegepant displayed signal-specific differences in antagonism of CGRP responses. This effect was also evident in transfected Cos7 cells, where olcegepant blocked CREB phosphorylation more potently than expected at the AMY1 receptor, suggesting that the affinity of this antagonist can be dependent on the signalling pathway activated. Conclusions CGRP receptor antagonist activity appears to be assay-dependent. Thus, these molecules may not be as selective for the CGRP receptor as commonly reported.
['Walker|Christopher S|CS|', 'Raddant|Ann C|AC|', 'Woolley|Michael J|MJ|', 'Russo|Andrew F|AF|', 'Hay|Debbie L|DL|']
D000818:Animals D019556:COS Cells D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists D002522:Chlorocebus aethiops D004151:Dipeptides D006801:Humans D009474:Neurons D010879:Piperazines D011799:Quinazolines D051381:Rats D017208:Rats, Wistar D018015:Receptors, Calcitonin Gene-Related Peptide D058287:Receptors, Islet Amyloid Polypeptide D015398:Signal Transduction D014162:Transfection D012668:Trigeminal Ganglion
calcitonin gene-related peptide (CGRP) migraine Amylin 1 (AMY1) trigeminal ganglia pain CREB bias