Migraines to the rescue! Research progress of CGRP and its receptor antagonists

Background

Migraine is a complex neurovascular disease that affects approximately 12% of the population each year to varying degrees. The main feature of the disease is severe headache, which may be accompanied by sensitivity to light (photophobia), Other symptoms such as voice sensitivity (fear of voice) and nausea. Activation of the trigeminal neurovascular system, which consists of nociceptive nerves from the first or ocular area of the trigeminal ganglion, major blood vessels responsible for regulating cerebral blood flow, and pain-sensitive areas of the brain, is currently considered to be the primary pathway leading to migraine. Made up of smaller blood vessels called the meninges. The trigeminal ganglion, on the other hand, is composed of pseudounipolar nerve cells, mainly Aδ and C-fibers, responsible for transmitting nociceptive messages from meningeal vessels to the caudal brainstem or the upper cervical spinal cord, thereby triggering headaches. Although the mechanism of migraine attack is not fully understood, it is widely believed that dysfunction of the central nervous system (CNS) leads to the release of inflammatory mediators that trigger sensitization and excitation of the trigeminal nerve, which in turn promotes neurogenic inflammation and pain stimuli . Activation of trigeminal nociceptors mediates the release of neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P, and neurokinin A. Studies have shown that these neuropeptides from primary sensory nerve fibers are involved in pain transmission the process of.

The mechanism of CGRP involved in the pathogenesis of migraine

According to the theory of migraine pathology, activation of nociceptive neurons in the trigeminal ganglion and subsequent release of CGRP are associated with migraine pathology. In humans, CGRP exists in two forms, called α-CGRP and β-CGRP, which are derived from different genes and differ by three amino acids but exhibit similar biological functions. The 37-amino acid neuropeptide α-CGRP is derived from alternative splicing of the calcitonin CGRP gene, is expressed in trigeminal ganglion neurons, and is thought to be a major component of migraine. In contrast, β-CGRP, encoded by a different gene with high homology to the calcitonin CGRP gene, is mainly expressed in the enteric nerve and pituitary gland, and its role in migraine is unclear.

CGRP is widely distributed in the central and peripheral nervous system, mainly expressed in C and Aδ nerve fibers, and transmits nociceptive signals to the central nervous system (CNS). Although the pathogenesis of migraine is not fully understood, some research evidence supports CGRP Functions as a key mediator of migraine pathology. For example, tests found that CGRP levels in both brain circulation and saliva increased during a migraine attack. While further data showed that the serotonin 1b/1D agonist sumatriptan, as well as other triptan drugs, successfully treated migraine headaches, resulted in normalization of CGRP levels, finally, studies have demonstrated that transfusion of human CGRP may be effective in susceptible individuals Intravenous CGRP receptor antagonist olcegepant (BIBN4096BS) can achieve the same level of efficacy in stopping acute migraine attacks as sumetriptan, which further proves that CGRP plays a key role in migraine . Given the central role of CGRP in migraine, blocking the physiological effects of CGRP and its receptors is a logical therapeutic strategy.

Current status of drug development

So far, a number of CGRP receptor antagonists have been used in clinical trials related to migraine treatment, including Boehringer Haier's olcegepant, Merck's Telcagepant (MK-0974), MK-3207, and Rimegepant developed by BMS, etc. , but were not successful, the main reason for their failure was the side effects of liver toxicity. Due to the hepatotoxic side effects of several previous drug candidates, Merck stopped development of its CGRP small molecule antagonist MK-1602 (ubrogepant) and transferred it to Allergan, who analyzed previous failures, arguing that hepatotoxicity was related to small molecule The structure of the antagonist is related, and the structure of ubrogepant is different from the previous failure cases, so the development of the drug was insisted on, and finally in 2019, it was successfully approved as the first CGRP small molecule receptor antagonist for the treatment of migraine.

Due to the previous setbacks in the development of small molecule antagonists of most CGRP receptors, a number of companies developed antibody drugs targeting CGRP and its receptors and caught up later. In 2018, Amgen's CGRP receptor antibody Aimovig was the first to be approved, becoming the first drug specifically for the treatment of migraine in the past 50 years, which is a milestone. After that, Teva and Lilly's CGRP antibodies Ajovy and Emgality were launched successively, and three similar products were approved in a short period of time.

In addition, Alder's Eptinezumab was approved in 2020, becoming the first intravenous treatment for migraine prevention.

For this important target in the treatment of migraine, we have developed a target-specific cell activity detection model, which can be used to screen and measure the activity of CGRP and its receptors at the cellular level of small and macromolecular drugs.

CALCR1/RAMP1/CRE-Luc/HEK293 RQP71361