MK-3207 is a potent and orally bioavailable CGRP receptor antagonist (IC50= 0.12 nM; Ki value= 0.024 nM), showing highly selective versus human AM1, AM2, CTR, and AMY3.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide involved in the pathophysiology of migraine. MK-3207 is a potent, orally bioavailable CGRP receptor antagonist. It exhibited high affinity for recombinant human receptor and for native human CGRP receptor in SK-N-MC cells with Ki values of 0.022 and 0.024nM, respectively. MK-3207 also displayed a similar affinity for rhesus monkey receptor with a Ki value of 0.024nM. In HEK293 cells expressing human CGRP receptor, MK-3207 inhibited human α-CGRP-stimulated cAMP responses with an IC50 value of 0.12±0.02nM. MK-3207 dose-dependently inhibited capsaicin-induced dermal blood flow in the rhesus monkey forearm with EC50 and EC90 values of 0.8 and 7nM, respectively. The IC50 value of MK-3207 in the human serum-shifted in vitro functional assay was 17nM[3].
作用机制
MK-3207 is a potent, highly selective, and orally bioavailable antagonist of human and rhesus monkey CGRP receptors. The receptor activity-modifying protein 1 (RAMP1) is a transmembrane-spanning protein responsible for the regulation of CGRP activity. The residue 74 on RAMP1 plays a key role in MK-3207 binding to CGRP receptor.
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