Engineering Na1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics.

Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel Na1.7, is being pursued to address the unmet medical need with respect to chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed Na1.

Discovery of Tarantula Venom-Derived Na1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis.

Inhibitors of the voltage-gated sodium channel Na1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified Na1.

The discovery of benzoxazine sulfonamide inhibitors of Na1.7: Tools that bridge efficacy and target engagement.

The voltage-gated sodium channel Na1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na1.

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel Na1.7.

Potent and selective antagonists of the voltage-gated sodium channel Na1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380.

Sulfonamides as Selective Na1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.

Because of its strong genetic validation, Na1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na1.

Cerebrovasodilation evoked by stimulation of subthalamic vasodilator area and hypoxia depends upon the integrity of cortical neurons in the rat.

In Sprague-Dawley rats symmetrical sites of the parietal cortex were microinjected with ibotenic acid (IBO, 10microg in 1microl) to lesion local neurons or with saline (1microl). Five days later, changes of cortical cerebral blood flow (CBF) in response to hypoxia and stimulation of the subthalamic vasodilator area (SVA) were measured using laser-Doppler flowmetry (LDF). The baseline CBF over the IBO- and saline-injected cortical sites did not differ significantly, but spontaneous waves of CBF were abolished over the lesioned sites.

Electrical stimulation of the dorsal periaqueductal gray decreases volume of the brain infarction independently of accompanying hypertension and cerebrovasodilation.

We investigated whether selective stimulation of neurons of the sympathoinhibitory ventral periaqueductal gray (VPAG), or sympathoexcitatory dorsal periaqueductal gray (DPAG), differentially modulates CBF and EEG and exerts neuroprotection. Electrical stimulation of either regions of PAG comparably elevated AP and CBF, whereas chemical stimulation with the D,L-homocysteine produced either sympathoinhibition accompanied by decrease in CBF from ventral region or sympathoexcitation accompanied by increase in CBF from dorsal region in nonspinalized rats. The CBF effects evoked from DPAG and VPAG by chemical stimulation were preserved in spinalized rats supporting that the evoked CBF responses result directly from stimulation and are not secondary to AP changes.