MK-3207 Hydrochloride (MK-3207 HCl) is a potent CGRP receptor antagonist with IC50 and Kiof 0.12 nM and 0.022 nM, highly selective versus human AM1, AM2, CTR, and AMY3. Phase 2.

CGRP:0.12 nM

MK 3207对天然和重组的人类CGRP受体以及恒河猴CGRP受体展现出显著较高的亲和力，其Ki值分别为24 pM、约24 pM和22 pM，相较于其他物种的CGRP受体（包括犬和啮齿类动物，Ki值约为10 nM）显示出更高的选择性。尽管MK 3207对AMY1（CTR/RAMP1）受体也有亲和力，Ki值为0.75 nM，但相较于其他相关的人类受体如AM1（CLR/RAMP2）、AM2（CLR/RAMP3）、AMY3（CTR/RAMP3）受体和CTR，其Ki值分别为16.5 μM、0.156 μM、0.128 μM和1.9 μM，显示出对人类CGRP受体的显著选择性。在稳定表达人类CLR/RAMP1的HEK293细胞中，MK 3207强效抑制由人α-CGRP诱导的cAMP产生，其IC50为0.12 nM，并且在含有50%人血清的环境下保持相似的效力（IC50为0.17 nM），表明MK 3207的活性不会因体内的血浆蛋白结合而受到显著影响。在人血清转移的体外功能测定中，MK 3207的效力大约是telcagepant的65倍，其IC50为10.9 nM。[1]

MK 3207 对恒河猴皮肤血管扩张的抑制作用呈浓度依赖性，能够阻断辣椒素诱导的血流量增加，其EC50为0.8 nM，EC90为7 nM。相比于telcagepant，在恒河猴辣椒素诱导的皮肤血管扩张(CIDV)评估中，MK 3207 显示出约100倍的增强效力，telcagepant的EC90为994 nM。[1]

Amylin binding assays are conducted by combining MK-3207 and 40 pM 125I-rat amylin, followed by 25 μg of CTR/RAMP1 or 25 μg of CTR/RAMP3 membranes and incubated for 3 h at room temperature in binding buffer (10 mM HEPES, 5 mM MgCl2, and 0.2% bovine serum albumin) in a total volume of 1 mL. Calcitonin binding assays are with 25 μg of CTR membranes and 30 pM 125I-human calcitonin as the radioligand. Incubations are terminated by filtration through GF/B 96-well filter plates that has been blocked with 0.5% polyethylenimine. Data are analyzed using Prism, and the Ki value is determined using the equation Ki=IC50/1 + ([ligand]/KD). The KD value for each receptor is determined by saturation binding experiments.