Telcagepant is an orally active antagonist of calcitonin gene-related peptide (CGRP) receptor (Kis: 0.77 nM and 1.2 nM for human and rhesus CGRP receptors, respectively).

CGRP (rhesus):1.2 nM(ki), CGRP (human):(ki)0.77 nM

Telcagepant shows affinity (Ki) for the canine and rat receptors, with values of 1204 nM and 1192 nM (n=10), respectively. Telcagepant displays saturable binding to SK-N-MC membranes with a KD of 1.9 nM and Bmax of 479 fmol/mg protein. Telcagepant effectively blocks human α-CGRP-stimulated cAMP responses in the human CGRP receptor-expressing HEK293 cells (IC50: 2.2 nM)[1]. Telcagepant also displays saturable binding to rhesus cerebellum homogenate (KD: 1.3 nM and Bmax of 20 fmol/mg)[2].

The pharmacokinetics of Telcagepant (MK-0974) remains linear across 0.5-10 mg/kg intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) enhances (5-30 mg/kg) is 15-fold over dose-proportional. Telcagepant (i.v. bolus, 1 mg/kg) demonstrates that the efficacy of this antagonist is time-dependent and correlated with plasma levels[1][3].