Donnette D. Staas

[(11)C]MK-4232: The First Positron Emission Tomography Tracer for the Calcitonin Gene-Related Peptide Receptor.

Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.

Calcitonin gene-related peptide receptor antagonists for the treatment of migraine: a patent review

Background: Migraine is a debilitating headache disorder which affects ∼ 12% of the general population and is the cause of significant loss of productivity (i.e., lost time from work or school) for those afflicted. The current standard of care, the 5-HT1B/1D agonists known as triptans, is contraindicated in patients with cardiovascular disease due to their inherent vasoconstrictive activity; thus, there is a need to develop an alternative therapy for the treatment of the disorder. Objective: This article reviews patent publications related to the use of small molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of migraine that have appeared in the literature within the past decade. The commentary is supplemented by information presented in journal articles and focuses on the activity of several major pharmaceutical companies in the field. Conclusion: Two small molecule CGRP receptor antagonists, olcegepant and telcagepant, have been shown to be clinically efficacious in the treatment of migraine, and thus provide validation of this novel therapeutic mechanism.

Kinetic Analysis of Membrane Potential Dye Response to NaV1.7 Channel Activation Identifies Antagonists with Pharmacological Selectivity against NaV1.5

The NaV1.7 voltage-gated sodium channel is a highly valued target for the treatment of neuropathic pain due to its expression in pain-sensing neurons and human genetic mutations in the gene encoding NaV1.7, resulting in either loss-of-function (e.g., congenital analgesia) or gain-of-function (e.g., paroxysmal extreme pain disorder) pain phenotypes. We exploited existing technologies in a novel manner to identify selective antagonists of NaV1.7. A full-deck high-throughput screen was developed for both NaV1.7 and cardiac NaV1.5 channels using a cell-based membrane potential dye FLIPR assay. In assay development, known local anesthetic site inhibitors produced a decrease in maximal response; however, a subset of compounds exhibited a concentration-dependent delay in the onset of the response with little change in the peak of the response at any concentration. Therefore, two methods of analysis were employed for the screen: one to measure peak response and another to measure area under the curve, which would capture the delay-to-onset phenotype. Although a number of compounds were identified by a selective reduction in peak response in NaV1.7 relative to 1.5, the AUC measurement and a subsequent refinement of this measurement were able to differentiate compounds with NaV1.7 pharmacological selectivity over NaV1.5 as confirmed in electrophysiology.