scholarly journals Fluorescent Analogues of Human α-Calcitonin Gene-Related Peptide with Potent Vasodilator Activity

2020 ◽  
Vol 21 (4) ◽  
pp. 1343 ◽  
Author(s):  
Jing Zhu ◽  
Mahdieh Dagina Pedersen ◽  
Laraib Sabbah Ahmed ◽  
Bahareh Abdolalizadeh ◽  
Anne-Sofie Grell ◽  
...  
Keyword(s):  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Calcitonin Gene Related Peptide ◽  
Receptor Internalization ◽  
Cgrp Receptor ◽  
Nociceptive Transmission ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Potent Vasodilator ◽  
Fluorescent Analogues

Human α-calcitonin gene-related peptide (h-α-CGRP) is a highly potent vasodilator peptide that belongs to the family of calcitonin peptides. There are two forms of CGRP receptors in humans and rodents: α-CGRP receptor predominately found in the cardiovascular system and β-CGRP receptor predominating in the gastrointestinal tract. The CGRP receptors are primarily localized to C and Aδ sensory fibers, where they are involved in nociceptive transmission and migraine pathophysiology. These fibers are found both peripherally and centrally, with extensive perivascular location. The CGRP receptors belong to the class B G-protein-coupled receptors, and they are primarily associated to signaling via Gα proteins. The objectives of the present work were: (i) synthesis of three single-labelled fluorescent analogues of h-α-CGRP by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis, and (ii) testing of their biological activity in isolated human, mouse, and rat arteries by using a small-vessel myograph setup. The three analogues were labelled with 5(6)-carboxyfluorescein via the spacer 6-aminohexanoic acid at the chain of Lys24 or Lys35. Circular dichroism (CD) experiments were performed to obtain information on the secondary structure of these fluorescently labelled peptides. The CD spectra indicated that the folding of all three analogues was similar to that of native α-CGRP. The three fluorescent analogues of α-CGRP were successfully prepared with a purity of >95%. In comparison to α-CGRP, the three analogues exhibited similar efficacy, but different potency in producing a vasodilator effect. The analogue labelled at the N-terminus proved to be the most readily synthesized, but it was found to possess the lowest vasodilator potency. The analogues labelled at Lys35 or Lys24 exhibited an acceptable reduction in potency (i.e., 3–5 times and 5–10 times less potent, respectively), and thus they have potential for use in further investigations of receptor internalization and neuronal reuptake.

Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons

Cephalalgia ◽  
2015 ◽  
Vol 35 (14) ◽  
pp. 1298-1307 ◽  
Author(s):  
P Pozo-Rosich ◽  
RJ Storer ◽  
AR Charbit ◽  
PJ Goadsby
Keyword(s):  
Receptive Fields ◽  
Periaqueductal Gray ◽  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Nociceptive Transmission ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Descending Influences ◽  
Dural Afferents

Background Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission. Methods The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP ( 8 – 37 ), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored. Results Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP ( 8 – 37 ) decreased them. Conclusions CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain.

Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity

2012 ◽  
Vol 108 (2) ◽  
pp. 431-440 ◽  
Author(s):  
Oana Covasala ◽  
Sören L. Stirn ◽  
Stephanie Albrecht ◽  
Roberto De Col ◽  
Karl Messlinger
Keyword(s):  
Trigeminal Ganglion ◽  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Afferent Input ◽  
Nitric Oxide Donor ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Trigeminal Neurons ◽  
Calcitonin Gene ◽  
Evoked Activity

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10−5 M), the CGRP receptor antagonist olcegepant (10−3 M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 μg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1

2012 ◽  
Vol 22 (14) ◽  
pp. 4723-4727 ◽  
Author(s):  
Xiaojun Han ◽  
Rita L. Civiello ◽  
Charles M. Conway ◽  
Deborah A. Cook ◽  
Carl D. Davis ◽  
...  
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists

scholarly journals Role of Calcitonin Gene Related Peptide (CGRP) in Migraine

2017 ◽  
Vol 33 (1) ◽  
pp. 39-43
Author(s):  
Md Ashraf Ali ◽  
Habibur Rahaman
Keyword(s):  
Family Relationships ◽  
Preventive Treatment ◽  
Primary Headache ◽  
Calcitonin Gene Related Peptide ◽  
Childhood And Adolescence ◽  
Protein Extravasation ◽  
Related Peptide ◽  
Plasma Protein Extravasation ◽  
Calcitonin Gene ◽  
Potent Vasodilator

Migraine is the second most primary headache. The prevalence of Migraine is 12% in the general population, including 18% in women and 6% in men. Migraine can start in childhood and adolescence and continue throughout lifespan. It is most prevalent among people in their 30s and 40s. Migraine is a debilitating hemicranial headache that is pulsating, aggravated by movement, nausea, vomiting and having sensitivity to light and sound, with or without aura. It can affect all aspects of life as work and school, parenting and family relationships and personal and leisure time. There are some theory regarding pathogenesis of migraine which includes cortical spreading depression, cortical spreading oligemia, activation of trigeminocervical complex leading to neuroinflammation & release of vasodialating neuropeptides which include calcitonin gene related peptide (CGRP), substance P, vasoactive intestinal polypeptide (VIP), nitric oxide (NO), and pituitary adenylate cyclase activating peptide (PACAP) & genetic factor. CGRP is a potent vasodilator and causes perivascular plasma protein extravasation and nociceptive pain. Newer medications target CGRP both for acute and preventive treatment of migraine. Bangladesh Journal of Neuroscience 2017; Vol.  33 (1): 39-43

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].

scholarly journals Effect of Calcitonin Gene-Related Peptide Receptor Antagonists on Migraine Treatment: A Meta-Analysis

2021 ◽  
Author(s):  
Jiyoung Kim ◽  
Kyoungjune Pak ◽  
Gha-Hyun Lee ◽  
Jae Wook Cho ◽  
Hyun-Woo kim
Keyword(s):  
Meta Analysis ◽  
Calcitonin Gene Related Peptide ◽  
Migraine Treatment ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Acute Migraine Treatment

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

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