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.

Olcegepant blocks neurogenic and non-neurogenic CGRPergic vasodepressor responses and facilitates noradrenergic vasopressor responses in pithed rats.[Pubmed:28369749]

Br J Pharmacol. 2017 Jul;174(13):2001-2014.

BACKGROUND AND PURPOSE: Olcegepant (BIBN4096BS) is a selective non-peptide CGRP receptor antagonist with acute antimigraine properties. Since systemic vascular tone is modulated by perivascular (primary sensory CGRPergic and sympathetic) nerves, this randomized study investigated in pithed rats the effect of acute i.v. treatment with Olcegepant on the neurogenic and non-neurogenic: (i) CGRPergic vasodepressor responses; and (ii) noradrenergic vasopressor responses. The pithed rat is an experimental model predictive of systemic (cardio) vascular side effects. EXPERIMENTAL APPROACH: Seventy-five male Wistar rats (divided into 15 groups, n = 5 each) were pithed, artificially ventilated and prepared for: (i) spinal stimulation (T9 -T12 ; 0.56-5.6 Hz) of the sensory CGRPergic vasodepressor outflow or i.v. bolus injections (0.1-1 mug.kg(-1) ) of alpha-CGRP, substance P or acetylcholine, which induced frequency-dependent or dose-dependent vasodepressor responses; or (ii) spinal stimulation (T7 -T9 ; 0.03-3 Hz) of the sympathetic vasopressor outflow or i.v. bolus injections (0.03-3 mug.kg(-1) ) of noradrenaline, which produced frequency-dependent or dose-dependent vasopressor responses. KEY RESULTS: Olcegepant (1000 and 3000 mug.kg(-1) , i.v.) dose-dependently blocked the vasodepressor responses to sensory nerve stimulation or i.v. alpha-CGRP, without affecting those to substance P or acetylcholine. Whereas it potentiated the vasopressor responses to sympathetic nerve stimulation or i.v. noradrenaline. CONCLUSIONS AND IMPLICATIONS: Olcegepant (i.v.) selectively blocked the neurogenic and non-neurogenic CGRPergic vasodepressor responses. This blockade by Olcegepant potentiated the neurogenic and non-neurogenic noradrenergic vasopressor responses in pithed rats, an effect that might result in an increased vascular resistance and, consequently, in a prohypertensive action.

Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat.[Pubmed:22795918]

Pain. 2012 Sep;153(9):1939-48.

Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of Olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3mg/kg, subcutaneously), Olcegepant (0.3 to 0.9mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with Olcegepant (0.3mg/kg intravenously) plus naratriptan (0.1mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.

Therapeutic effects and safety of olcegepant and telcagepant for migraine: A meta-analysis.[Pubmed:25206386]

Neural Regen Res. 2013 Apr 5;8(10):938-47.

OBJECTIVE: To evaluate the therapeutic effects and adverse reactions of Olcegepant and telcagepant for the treatment of migraine. DATA RETRIEVAL: We identified studies using Medline (1966-01/2012-06), PubMed (1966-01/2012-06), Scopus (1980-01/2012-06), Cochrane Central Register of Controlled Trials (1980-01/2012-06) and China National Knowledge Infrastructure (1980-01/2012-06). SELECTION CRITERIA: The included studies were double-blind, randomized and placebo-controlled trials of Olcegepant or telcagepant for the treatment of single acute migraine in patients with or without aura. Adverse reaction data were also included. Two independent investigators performed quality evaluation and data extraction using Jadad scoring. Meta-analyses were undertaken using RevMan 5.0.25 software. MAIN OUTCOME MEASURES: Pain relief rate, pain-free rate, and incidence of adverse reactions were measured in patients 2 and 24 hours after injection of Olcegepant and oral telcagepant. RESULTS: Six randomized, controlled trials were included. Meta-analysis demonstrated that compared with placebo, the pain relief rate (odds ratio, OR = 5.21, 95% confidence interval, CI: 1.91-14.2, P < 0.01) and pain-free rate (OR = 31.11, 95% CI: 3.80-254.98, P < 0.01) significantly increased 2 hours after 2.5 mg/d Olcegepant treatment. Pain relief rate and pain-free rate 2 and 24 hours after treatment with telcagepant 150 mg/d and 300 mg/d were superior to placebo (P < 0.01). Moreover, the remission rate of unrelenting headache was higher after 24 hours of 300 mg/d telcagepant treatment compared with 150 mg/d (OR = 0.78, 95% CI: 0.62-0.97, P < 0.05). The incidence of adverse reactions with Olcegepant was not significantly greater than placebo (P = 0.28), but within 48 hours of administration of telcagepant 300 mg/d, the incidence of adverse reactions was higher than placebo (OR = 1.21, 95% CI: 1.04-1.42, P < 0.01). Few studies have compared the therapeutic effects of Olcegepant and telcagepant. CONCLUSION: The calcitonin-gene-related peptide receptor antagonists Olcegepant and telcagepant have shown good therapeutic effects in the treatment of migraine. Moreover, the incidence of adverse reactions compares favorably with placebo, although liver transaminases may become elevated after long-term use.

CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.[Pubmed:28165287]

Cephalalgia. 2018 Mar;38(3):437-451.

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.

Olcegepant (BIBN-4096) is a potent and selective non-peptide antagonist of the calcitonin gene-related peptide 1 (CGRP1) receptor with IC50 of 0.03 nM and Ki of 14.4 pM for human CGRP.

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