J Pharmacol Exp Ther. 2010 Jan 11; Salvatore CA, Moore EL, Calamari A, Cook JJ, Michener MS, O'Malley S, Miller PJ, Sur C, Williams DL, Zeng Z, Danziger A, Lynch JJ, Regan CP, Fay JF, Tang YS, Li CC, Pudvah NT, White RB, Bell IM, Gallicchio SN, Graham SL, Selnick HG, Vacca JP, Kane SACalcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology and the advent of small molecule antagonists have clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. MK-3207 [2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide] represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists MK-3207 displays lower affinity for CGRP receptors from other species including canine and rodent. As a consequence of species selectivity the in vivo potency was assessed in a rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. A tritiated analog, [(3)H]MK-3207, was used to study the binding characteristics on the human CGRP receptor. [(3)H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM) and the off-rate was determined to be 0.012 min(-1) with a t(1/2) of 59 min. In vitro autoradiography studies on rhesus brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of CNS penetrability, the in vivo CSF/plasma ratio was determined to be 2-3% in cisterna magna-ported rhesus monkeys.
