Other meanings of CGRP receptor antagonist
Pharmacology
CGRP receptor antagonists are a class of drugs that block the calcitonin gene-related peptide (CGRP) receptor, primarily used for the acute and preventive treatment of migraine. By inhibiting CGRP signaling, these agents reduce vasodilation and neurogenic inflammation implicated in migraine pathophysiology. The class includes small-molecule gepants (e.g., ubrogepant, rimegepant) and monoclonal antibodies (e.g., erenumab) that target the receptor, offering targeted relief with fewer cardiovascular side effects than older treatments.
CGRP receptor antagonists bind to the CGRP receptor, a G protein-coupled receptor composed of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). This binding prevents CGRP from activating the receptor, thereby blocking downstream signaling pathways that lead to vasodilation, plasma protein extravasation, and nociceptive transmission in trigeminal neurons.1 Unlike triptans, which cause vasoconstriction, these antagonists do not constrict blood vessels, making them safer for patients with cardiovascular disease.2 The selectivity for the CGRP receptor over other calcitonin family receptors is crucial for minimizing off-target effects.
Gepants are used for acute treatment (ubrogepant, rimegepant) and preventive therapy (atogepant, rimegepant) of episodic and chronic migraine. Monoclonal antibodies like erenumab, which target the receptor, are administered monthly or quarterly for prevention.3 Clinical trials show significant reductions in migraine days and improved quality of life compared to placebo.4 Common adverse effects include nausea, fatigue, and constipation, but they are generally well-tolerated. Unlike triptans, they do not carry a risk of serotonin syndrome or cardiovascular events, expanding treatment options for patients with contraindications.
The first gepant, olcegepant, was developed in the early 2000s but failed in trials due to poor oral bioavailability and hepatotoxicity.5 Subsequent efforts led to telcagepant, which showed efficacy but was discontinued due to liver enzyme elevations.6 These setbacks prompted a shift toward monoclonal antibodies, which have a different safety profile. Later, second-generation gepants with improved pharmacokinetics were developed, leading to FDA approvals starting in 2018 with erenumab, followed by ubrogepant (2019), rimegepant (2020), and atogepant (2021). The evolution reflects a broader trend toward targeted, mechanism-based migraine therapies.
Beyond migraine, CGRP receptor antagonists are being explored for other conditions, including cluster headache and temporomandibular joint disorders.3 Some studies suggest they may have a role in treating opioid-induced hyperalgesia.1 The CGRP receptor is also expressed in the cardiovascular system, but clinical data show no increased risk of cardiovascular events, contrary to early theoretical concerns.2 Additionally, the discovery of CGRP's role in migraine was serendipitous, stemming from research on calcitonin gene expression in the 1980s. These agents also highlight the importance of RAMP1 in receptor pharmacology, as its expression levels can modulate drug efficacy.
CGRP receptor antagonists represent a paradigm shift in migraine therapy, offering targeted, non-vasoconstrictive options.
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