Antagonism of CGRP Signaling by Rimegepant at Two Receptors

Pan, Kylie S; Siow, Andrew; Hay, Debbie L.; Walker, Christopher S.

doi:10.3389/fphar.2020.01240

Cited by 38 publications

(47 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With respect to AMY 1 receptor signaling, both erenumab and telcagepant antagonized human amylin-induced signaling at the AMY 1 receptor. It has been long known that many small molecule antagonists designed to target the CGRP receptor also block activity at the AMY 1 receptor ( 19 , 20 , 30 – 32 ). Antagonism at both the CGRP and AMY 1 receptors has been shown for rimegepant ( 32 ) and ubrogepant ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…It has been long known that many small molecule antagonists designed to target the CGRP receptor also block activity at the AMY 1 receptor ( 19 , 20 , 30 – 32 ). Antagonism at both the CGRP and AMY 1 receptors has been shown for rimegepant ( 32 ) and ubrogepant ( 33 ). Downstream signaling pathways and in turn pharmacological responses of all GPCRs, including the CGRP-family of receptors, are very highly dependent on the cellular context of differing recombinant cell lines and expression systems ( 20 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Migraine therapeutics differentially modulate the CGRP pathway

et al. 2021

View full text Add to dashboard Cite

Background The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. Methods To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. Results Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. Conclusion The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Migraine therapeutics differentially modulate the CGRP pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Amylin signaling is not covered in depth here, but has been reported to be a part of the TVS [27]. Amylin receptors could therefore play a part as a CGRP target, and indeed some antimigraine drugs, such as rimegepant, also bind the amylin receptor [28]. Here, we focus further on the potential cellular targets for CGRP, which include the middle meningeal artery [29], satellite glial cells [30], and importantly, Aδ neurons [31].…”

Section: Reducing the Effect Of Neuropeptidesmentioning

confidence: 99%

Identifying New Antimigraine Targets: Lessons from Molecular Biology

Edvinsson

Haanes

2021

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

show abstract

“…The adrenomedullin 1 and 2 receptors differ by having a different RAMP unit (RAMP2 and RAMP3, respectively, instead of RAMP1 for the CGRP receptor). Recently, rimegepant was found to be able to target the AMY1 receptor as well, albeit with a lower potency [46]. The role of the AMY1 receptor in migraine needs to be investigated further and the effects of blocking this receptor should be identified.…”

Section: Expert Opinionmentioning

confidence: 99%

Evaluating rimegepant for the treatment of migraine

Vries

Al-Hassany

MaassenVanDenBrink

2021

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

IntroductionCalcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide involved in the pathophysiology of migraine, a highly disabling neurovascular disorder characterized by severe headache attacks. Rimegepant is a small-molecule CGRP receptor antagonist approved by the FDA for acute treatment of migraine and currently under investigation for migraine prophylaxis. Areas coveredThe authors summarize available data on safety and tolerability of rimegepant and provide insights on its use for acute migraine treatment. Expert opinion Rimegepant seems to be well tolerated and superior to placebo for two-hour pain freedom. Moreover, rimegepant does not induce vasoconstriction, and is therefore not contraindicated in patients with cardiovascular disease, nor does it seem to induce medication-overuse headache. However, the therapeutic gain of rimegepant is only small, and since CGRP is a vital rescue molecule during ischemia, blocking the CGRP pathway might be detrimental. Although current evidence on CGRP receptor blockade has shown no cardiovascular adverse events, clinicians should remain critical about the use of rimegepant, as well as other CGRP (receptor)-inhibiting drugs. Further research should focus on determining the consequences of long-term CGRP blockade, especially during ischemia or cardiovascular disease, the exact receptors antagonized by rimegepant, and potential effects of combining rimegepant with other antimigraine treatments.

show abstract

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

Cited by 38 publications

References 19 publications

Migraine therapeutics differentially modulate the CGRP pathway

Migraine therapeutics differentially modulate the CGRP pathway

Identifying New Antimigraine Targets: Lessons from Molecular Biology

Evaluating rimegepant for the treatment of migraine

Contact Info

Product

Resources

About