Telcagepant (MK-0974) is an oral calcitonin gene-related peptide receptor (CGRP) antagonist that blocks CGRP receptors and reduces neurotransmission in the central nervous system and is used in the study of migraines and for pain relief.

CGRP-induced cAMP accumulation (human CGRP receptor-expressing HEK293 cells, 50% human serum):10.9  nM, Capsaicin-induced vasodilation via CGRP receptor (rhesus monkey):994  nM (EC₉₀), CGRP (rhesus):1.2 nM (ki), CGRP-induced cAMP accumulation (human CGRP receptor-expressing HEK293 cells):2.2  nM, Capsaicin-induced vasodilation via CGRP receptor (rhesus monkey):127  nM (EC₅₀), Capsaicin-induced vasodilation via CGRP receptor (rhesus monkey):0.77 nM (ki)

The in vitro activity of Telcagepant was evaluated in HEK293 cells stably expressing the human CGRP receptor (CLR/RAMP1). Cells were pretreated with Telcagepant for 30 minutes, followed by stimulation with α-CGRP (0.3 nM) for 5 minutes to assess cAMP levels. Telcagepant inhibited CGRP-induced cAMP accumulation in a concentration-dependent manner with an IC₅₀ of 2.2 nM, increasing to 10.9 nM in the presence of 50% human serum. Radioligand binding assays confirmed high affinity for human CGRP receptors (Ki = 0.77 nM) and much lower affinity for dog and rat receptors (Ki > 1200 nM), indicating strong species selectivity [1].

The in vivo activity of Telcagepant was assessed in a rhesus monkey dermal vasodilation model. Monkeys received intravenous Telcagepant (0.03–3.7 mg/kg bolus followed by 0.13–20 μg/kg/min infusion), and capsaicin (2 mg) was applied topically to induce dermal blood flow via endogenous CGRP release. Laser Doppler imaging showed that Telcagepant inhibited capsaicin-induced vasodilation in a plasma concentration-dependent manner, with calculated EC₅₀ and EC₉₀ values of 127 nM and 994 nM, respectively, confirming in vivo CGRP receptor blockade [1].