Abstract
The “gepants” are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY1 receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY1, and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY1 receptor. The antagonism of both CGRP and AMY1 receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.
Highlights
Rimegepant (BHV-3000; formerly BMS-927711) is a small molecule drug that has recently been approved as a treatment for migraine (Scott, 2020)
Rimegepant antagonism at calcitonin gene-related peptide (CGRP) and AMY1 receptors was compared with two approaches
Schild analysis was conducted with multiple concentrations of rimegepant against a range of aCGRP concentrations at both receptors and amylin concentrations at the AMY1 receptor (Figure 2, Table 1)
Summary
Rimegepant (BHV-3000; formerly BMS-927711) is a small molecule drug that has recently been approved as a treatment for migraine (Scott, 2020) It is a member of the “gepant” class of molecules which antagonize the activity of the neuropeptide calcitonin gene-related peptide (CGRP) (Luo et al, 2012; Hargreaves and Olesen, 2019). Monoclonal antibodies and orally bioavailable small molecule antagonists, including rimegepant, are approved as migraine therapeutics (Luo et al, 2012; Hargreaves and Olesen, 2019). These therapeutics reduce CGRP signaling by preventing receptor activation. The ability of rimegepant to antagonize CGRP activity at the AMY1 receptor has not been published (Hay et al, 2018), a recent report implied that
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