Pharmacological Characterization of MK-0974 [N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine

Salvatore, Christopher; Hershey, James C.; Corcoran, Halea A.; Fay, John F.; Johnston, Victor K.; Moore, Eric L.; Mosser, Scott D.; Burgey, Christopher S.; Paone, Daniel V.; Shaw, A.; Graham, Samuel; Vacca, Joseph P.; Williams, Theresa M.; Koblan, Kenneth S.; Kane, Stefanie A.

doi:10.1124/jpet.107.130344

Cited by 137 publications

(121 citation statements)

References 26 publications

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“…Data from a clinical proof-of-concept study demonstrate the effectiveness of olcegepant in the acute treatment of migraine, with the response rate being similar to oral triptans (Olesen et al 2004). These lines of evidence are in accordance with recent findings in a larger, ramdomized controlled trial of the orally available CGRP receptor antagonist MK-0974 (Ho et al 2008), which, similar to olcegepant, is a potent antagonist of the human CGRP receptors (Salvatore et al 2008). Since olcegepant does not induce vasoconstriction per se, this CGRP receptor antagonist has been argued to be safer than triptans, particularly in migraineurs suffering from cardiovascular pathologies.…”

Section: Cgrp Receptorssupporting

confidence: 90%

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 Receptorssupporting

confidence: 90%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…HEK293 cells stably expressing the human CGRP (CLR/RAMP1) receptor was described in previous work (Salvatore et al, 2008). Parental HEK293 and cells stably expressing the human CGRP receptor were plated on Poly-D-Lysine 8-well CultureSlides (BD Biosciences, San Jose, CA) and cultured overnight at +37°C in a CO 2 incubator.…”

Section: Immunostaining Of Cell Linesmentioning

confidence: 99%

“…HEK293 cells stably expressing the human CGRP (CLR/RAMP1) receptor was previously described in Salvatore et al (2008). For transient transfections, 24 h prior to transfection HEK293 cells were seeded in 500 cm 2 dishes.…”

Section: Cell Culture and Generation Of Recombinant Cell Linesmentioning

confidence: 99%

Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

et al. 2010

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"Differential distribution of calcitonin gene-related peptide (CGRP) and CGRP receptor components (CLR and RAMP1) in the human trigeminal ganglion."Neuroscience, 2010, Jun 2 http://dx.doi.org/10.1016/j.neuroscience.2010.05.016Access to the published version may require journal subscription.Published with permission from: Elsevier Antibodies against purified CLR and RAMP1 proteins were produced and characterized for this study. Trigeminal ganglia were obtained at autopsy from adult subjects and sections from rat trigeminal ganglia were used to compare the immunostaining pattern. The number of cells expressing CGRP, CLR and RAMP1, respectively, were counted. In addition, the glial cells of trigeminal ganglion, particularly the satellite glial cell, were studied to understand a possible relation.We observed immunoreactivity for CGRP, CLR and RAMP1, in the human trigeminal ganglion: 49% of the neurons expressed CGRP, 37% CLR and 36% RAMP1. Co-localization of CGRP and the receptor components was rarely found. There were no CGRP immunoreactions in the glial cells; however some of the glial cells displayed CLR and RAMP1 immunoreactivity. Similar results were observed in rat trigeminal ganglia.We report that human and rat trigeminal neurons store CGRP, CLR and RAMP1, however, CGRP and CLR/RAMP1 do not co-localize regularly but are found in separate neurons. Glial cells also contain the CGRP receptor components but not CGRP. Our results indicate, for the first time, the possibility of CGRP signaling in the human trigeminal ganglion involving both neurons and satellite glial cells. This suggests a possible site of action for the novel CGRP receptor antagonists in migraine therapy.

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“…It is a potent selective antagonist of the human (K i ϭ 0.77 nmol/L) and rhesus monkey (K i ϭ 1.2 nmol/L) CGRP receptors, but displays Ͼ1500-fold lower affinity for the canine and rat receptors as determined via [ 125 I]-human CGRP competition binding assays. 89 Telcagepant potently blocked ␣-CGRP-stimulated cAMP responses in human CGRP receptor-expressing HEK293 cells with an IC 50 of 2.2 Ϯ 0.29 nmol/L. The unbound fraction in plasma was 4.1% in human plasma.…”

Section: Clinical Studies Of Cgrp Receptor Antagonistsmentioning

confidence: 99%

CGRP Receptor Antagonism and Migraine

Edvinsson

2010

Neurotherapeutics

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Summary: Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. ␣CGRP is prominently localized in primary spinal afferent C and A⌬ fibers of sensory ganglia, and ␤CGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

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Cited by 137 publications

References 26 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

CGRP Receptor Antagonism and Migraine

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