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Recently, the FDA approved ubrogepant and rimegepant as oral drugs to treat migraines by targeting the calcitonin-gene related peptide receptor (CGRPR). Unfortunately, there is no high-resolution complex structure with these two drugs; thus the detailed interaction between drugs and the receptor remains elusive. This study uses molecular docking and molecular dynamics simulation to model the drug-receptor complex and analyze their binding interactions at a molecular level. The complex crystal structure (3N7R) of the gepant drugs' predecessor, olcegepant, was used for our molecular docking of the two drugs and served as a control system. The three systems, with ubrogepant, rimegepant, and crystal olcegepant, were subject to 3 × 1000 ns molecular dynamics simulations and followed by the simulation interaction diagram (SID), structural clustering, and MM-GBSA binding energy analyses. Our MD data revealed that olcegepant binds most strongly to the CGRPR, followed by ubrogepant and then rimegepant, largely due to changes in hydrophobic and electrostatic interactions. The order of our MM-GBSA binding energies of these three compounds is consistent with their experimental IC 50 values. SID analysis revealed the pharmacophore of the gepant class to be the dihydroquinazolinone group derivative. Subtle differences in interaction profile have been noted, including interactions with the W74 and W72 residues. The ubrogepant and rimegepant both contact A70 and M42 of the receptor, while olcegepant does not. The results of this study elucidate the interactions in the binding pocket of CGRP receptor and can assist in further development for orally available antagonists of the CGRP receptor.

Introduction Calcitonin 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 covered The 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.

Introduction : Migraine is one of the most common neurological disorders. Nowadays, the 5-HT 1B/1D receptor agonists, namely triptans, are considered as the standard of care for migraine acute treatment. However, triptans have limitations in some patients, such as incomplete pain relief, headache recurrence, and cardiovascular contraindications. New 5-HT 1F receptor agonists, namely ditans, and calcitonin gene-related peptide receptor antagonists, namely gepants, have been developed as migraine-specific treatments. Areas covered : This paper reviews the available data from RCTs to assess the clinical efficacy, safety, and tolerability profile of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine and atogepant for the prevention of migraine. Expert opinion : Available data suggest that lasmiditan, rimegepant, and ubrogepant might not have a clinical efficacy similar to triptans. Lasmiditan did not cause the typical triptan side effects but was associated with central nervous system side effects, causing temporary driving impairment. On the contrary, the new generation of gepants showed a placebo-like tolerability profile and the absence of a specific pattern of side effects. Future studies on lasmiditan and gepants with respect to established effective comparators are mandatory to support phase III results and to help clinicians to balance the benefit/risk profiles of the various acute and preventive medications.

Migraine headache treatment is quickly evolving. There have been three new acute migraine treatment options (i.e., lasmiditan, rimegepant, ubrogepant) and four new preventive migraine treatment options (i.e., erenumab, fremanezumab, galcanezumab, eptinezumab) released in the past 3 years. The new migraine treatments are focusing on pathways within the newly, better understood neurovascular hypothesis that further describes the pathophysiology of migraine headaches in more detail than before. The discovery of vasoactive peptides, such as calcitonin gene-related peptide, has led to the development of many of these migraine agents. Rimegepant is one of these newly approved agents for acute migraine treatment in adults with or without aura. Rimegepant has been found to decrease pain and symptoms associated with migraine attacks and is generally well-tolerated.

Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist developed with a novel quick-dissolve oral tablet formulation for the acute treatment of migraine by Biohaven Pharmaceuticals, under license from Bristol Myers Squibb. The completed phase II and III trials showed its efficacy in terms of pain freedom, pain relief, release of migraine symptoms and lifestyle recovery, with an effect sustained up to 48 h. Significant clinical efficacy has been reported with a rimegepant single dose. Rimegepant was well tolerated and the few adverse events were mild or moderate and did not cause trial discontinuation. It received Food and Drug Administration (FDA) approval on February 27, 2020, for the acute treatment of migraine headache. Three clinical trials are currently ongoing to evaluate: i) the long-term safety as migraine acute treatment; ii) the efficacy and safety as a preventive treatment for migraine; and iii) the efficacy and safety for refractory trigeminal neuralgia. Future studies should be designed also to evaluate potential drug-drug interactions., (Copyright 2020 Clarivate Analytics.)

Two randomized clinical trials showed that calcitonin gene-related peptide targeting therapies are effective and safe for primary headache disorders. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development., Areas Covered: This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs., Expert Opinion: Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.

Introduction: Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration)., Areas Covered: This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data., Expert Opinion: Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.