scholarly journals CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured

Cephalalgia ◽  
2017 ◽  
Vol 38 (3) ◽  
pp. 437-451 ◽  
Author(s):  
Christopher S Walker ◽  
Ann C Raddant ◽  
Michael J Woolley ◽  
Andrew F Russo ◽  
Debbie L Hay
Keyword(s):  
Receptor Antagonist ◽  
Signalling Pathway ◽  
Cgrp Receptor ◽  
Trigeminovascular System ◽  
Antagonist Activity ◽  
Creb Phosphorylation ◽  
Signalling Molecules ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist

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.

Novel Therapies in Acute Migraine Management: Small-Molecule Calcitonin Gene-Receptor Antagonists and Serotonin 1F Receptor Agonist

2020 ◽  
pp. 106002802096357
Author(s):  
Kayla Rena Joyner ◽  
Kelsey Woods Morgan
Keyword(s):  
Receptor Antagonist ◽  
English Language ◽  
Data Extraction ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Study Selection ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist

Objective To review the efficacy, safety, and cost of 3 newly approved agents—ubrogepant, lasmiditan, and rimegepant—representing 2 therapeutic classes, calcitonin gene-related peptide (CGRP) receptor antagonist and serotonin 1F (5-HT1F) agonists, for the acute treatment of migraine with or without aura. Data Sources The Institute of Health US National Library of Medicine Clinical Trials, PubMed, and Cochrane databases were queried. Abstracts, journal articles, and other relevant sources published or present were reviewed. Search terms included the following: ubrogepant, MK-1602, Ubrelvy®, rimegepant, Nurtec®, BHV-3000, BMS-927711, lasmiditan, Reyvow®, LY573144. Study Selection and Data Extraction Relevant English-language articles from June 30, 2010, to August 31, 2020, were evaluated and included in the narrative. Data Synthesis CGRP receptor antagonists, ubrogepant and rimegepant, achieved 2-hour pain freedom and freedom from the most bothersome migraine symptom (MBS) at 2 hours. Both agents were well tolerated, with adverse effects similar to placebo. Lasmiditan, a 5-HT1F receptor antagonist, also improved 2-hour pain freedom and freedom from the MBS at 2 hours. Lasmiditan is associated with dizziness, paresthesia, somnolence, nausea, fatigue, and lethargy. Relevance to Patient Care and Clinical Practice Ubrogepant, rimegepant, and lasmiditan represent a new and exciting chapter in acute migraine therapy. To date, no head-to-head studies have compared these agents with the triptans. Ubrogepant and lasmiditan are effective in triptan nonresponders. None of the 3 agents is contraindicated in cardiovascular disease, unlike the triptans. Conclusions Based on available data, ubrogepant, rimegepant, and lasmiditan should be reserved as second-line therapy and may be safe in patients with cardiovascular risk. Lasmiditan’s adverse effect profile may limit its use.

scholarly journals A Short on Ubrogepant

2021 ◽  
pp. 79-81
Author(s):  
S. Padmaja ◽  
J. Mohan
Keyword(s):  
Receptor Antagonist ◽  
Research Process ◽  
Calcitonin Gene Related Peptide ◽  
Review Article ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Acute Attacks ◽  
Cgrp Receptor Antagonist

Migraine is a mysterious disorder characterized by pulsating head ache, which is actually characterized to one side and comes in attacks which will be lasting for about 3-48 hours and can be associated with nausea,vomiting,sensitivity to sound,flashes of light,vertigoand diarrhoea [1]. Most of the drugs which are in current use for actue migraine like triptans, treats the disorder symptomatically. A novel group of drugs has been in research for the migraine which treats the disorder pathologically. Calcitonin gene – related peptide (CGRP) has a major role in the pathophysiology of the disorder and hence CGRP receptor antagonist, known as Gepants are in the research process [2]. Gepants are being studied for the efficacy of treating acute migraine [2]. This article will be a review article about the drug – Ubrogepant, which is approved for treatment of migraine with acute attacks in adults [3].

Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia

Cephalalgia ◽  
2013 ◽  
Vol 34 (8) ◽  
pp. 594-604 ◽  
Author(s):  
R Greco ◽  
AS Mangione ◽  
F Siani ◽  
F Blandini ◽  
M Vairetti ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Formalin Test ◽  
Tail Flick ◽  
Cgrp Receptor ◽  
Tail Flick Test ◽  
Nociceptive Transmission ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist ◽  
Trigeminal Nerves

Background The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. Aim The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. Results MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30–60 minutes before) NTG. Conclusion These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.

Zavegepant. Calcitonin gene-related peptide (CGRP) receptor antagonist, Treatment of migraine

2021 ◽  
Vol 46 (4) ◽  
pp. 281
Author(s):  
F. Cipolla ◽  
M. Capi ◽  
L. Lionetto ◽  
D. De Bernardini ◽  
V. De Angelis ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist

Rimegepant. Calcitonin gene-related peptide (CGRP) receptor antagonist, Treatment of migraine

2019 ◽  
Vol 44 (8) ◽  
pp. 635 ◽  
Author(s):  
L. Lionetto ◽  
M. Capi ◽  
M. Curto ◽  
F. Cipolla ◽  
M. Guglielmetti ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist

Calcitonin gene related peptide as inhibitory neurotransmitter in the ureter

1995 ◽  
Vol 73 (7) ◽  
pp. 986-990 ◽  
Author(s):  
C. A. Maggi ◽  
S. Giuliani ◽  
S. Meini ◽  
P. Santicioli
Keyword(s):  
Guinea Pig ◽  
Receptor Antagonist ◽  
Calcitonin Gene Related Peptide ◽  
K Channel ◽  
Organ Bath ◽  
Cgrp Receptor ◽  
Membrane Hyperpolarization ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist

A dense plexus of calcitonin gene related peptide (CGRP) containing nerve fibres is present in the mammalian ureter, from which CGRP is released by depolarizing stimuli, including chemicals normally present in the urine. CGRP exerts a profound, receptor-mediated, inhibitory effect on the evoked motility of the ureter by suppressing latent pacemakers in the smooth muscle. This effect is largely glibenclamide sensitive, indicating the activation of potassium (K) channels in its genesis. Electrical stimulation of intramural nerves in the guinea-pig ureter produces a transient membrane hyperpolarization, which is blocked by glibenclamide or by capsaicin pretreatment, enhanced in a low-K medium, and inhibited by a CGRP receptor antagonist. Thus endogenous CGRP acts as a neurotransmitter K channel opener in the ureter. The refractory period of the guinea-pig ureter is markedly and similarly reduced by capsaicin pretreatment or administration of a CGRP receptor antagonist, indicating that endogenous CGRP can modulate the maximal frequency of ureteral peristalsis. Using a three-chamber organ bath that enabled the separate perfusion of the renal, middle, and bladder regions of the organ, evidence was obtained that CGRP blocks propagation of impulses along the ureter through a glibenclamide-sensitive mechanism. These findings indicate a role of CGRP in the local regulation of ureteral motility and peristalsis.Key words: guinea-pig ureter, calcitonin gene related peptide, sensory nerves, glibenclamide-sensitive potassium channels.

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