Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist

Doods, Henri; Hallermayer, Gerhard; Wu, Dongmei; Entzeroth, Michael; Rudolf, K; Engel, Wolfhard; Eberlein, Wolfgang

doi:10.1038/sj.bjp.0703110

Cited by 438 publications

(370 citation statements)

References 17 publications

(18 reference statements)

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“…An important breakthrough in the field of CGRP was the development of the potent and selective CGRP receptor antagonist olcegepant (BIBN4096BS; Doods et al 2000). In in vivo animal models of migraine, olcegepant attenuated the vasodilation induced by trigeminal stimulation and capsaicin-induced carotid arteriovenous anastomotic dilatation Edvinsson 2004;Kapoor et al 2003;Petersen et al 2005b).…”

Section: Cgrp Receptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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Section: Cgrp Receptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…More recently, Grant et al (2004) reported that exogenously administered haCGRP triggers, in the arterial mesenteric bed of the mouse, a marked vasodilatation which was abolished by BIBN4096BS (1-piperidinecarboxamide, N-[2- [ [5-amino-1-[ [4-(4- (Doods et al, 2000). It is however worthy of mention that the contribution of the endothelium in these vasoactive responses to CGRP in the mouse mesenteric circuit was not explored by this group.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Legros

Tirapelli

Brochu

et al. 2007

British J Pharmacology

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Background and purpose: Calcitonin gene-related peptide (CGRP), a capsaicin-sensitive neuromodulator of splanchnic vascular tone in several animal species, remains poorly investigated in mouse models. We therefore assessed whether endogenous CGRP is a non-adrenergic/non-cholinergic (NANC) neuromodulator in the mesenteric vascular bed of the mouse. Experimental approach: Arterial and venous changes in perfusion pressure in response to perivascular nerve stimulation (PNS) were monitored in the mouse mesenteric bed under basal conditions or precontracted with KCl (artery) or U46619 (vein) in circuits pretreated with guanethidine, atropine, indomethacin and prazosin. Arterial responses to NANC were also characterized with a CGRP1 antagonist, haCGRP 8À37. Finally, the PNS-induced release of arterial CGRP was measured by enzyme immunoassay. Key results: HaCGRP 8À37 enhanced PNS-induced arterial increases in perfusion pressure under basal tone. PNS-induced stimulation of NANC triggered an haCGRP 8À37 or capsaicin-sensitive reduction in perfusion pressure of the pre-contracted arterial bed only. Chemical removal of the endothelium inhibited PNS-and haCGRP-induced reduction in perfusion pressure in the arterial mesenteric bed. Responses to NANC nerves were reduced by guanylate and adenylate cyclase inhibitors (1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (ODQ)) and [9-(tetrahydro-2-furanyl)-9H-purin-6-amine] (SQ 22 536), respectively. A neuronal NOS inhibitor (7-nitroindazole; 7-NI) also enhanced the response to NANC in vessels from wild-type, eNOS KO but not iNOS KO mice. Finally, PNS enhanced the release of immunoreactive CGRP from the perfused arterial mesenteric bed. Conclusions and implications: Our study demonstrates a role for CGRP in the NANC-dependent reduction in perfusion pressure of the arterial but not venous mesenteric bed of the mouse. (2007) Keywords: CGRP; haCGRP 8À37 ; neuronal nitric oxide synthase; arterial mesenteric vasculature; mouse model British Journal of Pharmacology

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“…Doods et al [71] described the first potent and selective non-peptide human CGRP-receptor antagonist (RA): BIBN4096BS, later renamed olcegepant. Prior to that, N-terminal-truncated CGRP fragments have been described as antagonists, but with limited use in vivo because of their short half-life, lower affinity, and non-selectiveness [20,72].…”

Section: Cgrp Receptor Antagonistsmentioning

confidence: 99%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs). Key PointsThe neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack.Targeting CGRP as a specific therapeutic tool for migraine may offer similar or even better efficacy than currently available treatments without the vasoconstrictive risk factors.Further studies are necessary to determine the exact role of CGRP receptor antagonists and CGRP monoclonal antibodies in migraine with aura, allodynia, and photophobia.

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Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist

Cited by 438 publications

References 17 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Targeting CGRP: A New Era for Migraine Treatment

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