Olcegepant

Olcegepant Description:IC50: 0.1nM on human brain vessels [1]
Olcegepant is the first potent and selective non-peptide antagonist of the calcitonin gene-related peptide 1 (CGRP1) receptor, a key modulator in neurogenic inflammatory pain. Under development by Boehringer Ingelheim GmbH, olcegepant is an intravenously formulated treatment for acute attacks of migraine.
In vitro: Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP- (8-37) and olcegepant with pA2 values of 7.8 and 11.2, respectively. [1].
In vivo: Pre-treatment with olcegepant (900 mg/kg) inhibited the capsaicin-induced expression of Fos throughout the spinal trigeminal nucleus by 57%. In contrast, the expression of phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion was not changed by olcegepant pre-treatment. CGRP receptor inhibition, which has been shown to decrease spinal trigeminal activity, is likely to occur in the central nervous system rather than in the periphery including the trigeminal ganglion. This may be important for future therapeutic interventions with CGRP receptor antagonists in migraine. [2].
Clinical trial: In a phase II clinical trial, olcegepant reduced the severity of headache in 60% of migraine sufferers and met secondary endpoints including headache-free rate and rate of sustained response. Only mild-to-moderate transient adverse events were observed, with no adverse cardiovascular symptoms reported. The compound appears to be an effective anti-migraine medication that is well tolerated and does not display the vasoconstrictive effect that precludes the use of triptans and dihydroergotamine in certain patients [3].
Reference:
[1] Edvinsson L, Alm R, Shaw D, Rutledge RZ, Koblan KS, Longmore J, Kane SA. Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur J Pharmacol. 2002;434(1-2):49-53.
[2] Sixt ML, Messlinger K, Fischer MJ. Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. Brain. 2009;132(Pt 11):3134-41.
[3] Recober A, Russo AF. Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007;10(8):566-74.