Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.     

Adrenergic stimulation of Na+ transport across alveolar epithelial cells involves activation of apical Cl- channels

Alveolar epithelial cells were isolated from adultSprague-Dawley rats and grown to confluence on membrane filters. Mostof the basal short-circuit current(I_sc; 60%) wasinhibited by amiloride (IC₅₀ 0.96 µM) or benzamil (IC₅₀ 0.5 µM).Basolateral addition of terbutaline (2 µM) produced a rapid decreasein I_sc, followed by a slow recovery back to its initial amplitude. WhenCl was replaced withmethanesulfonic acid, the basalI_sc was reduced and the response to terbutaline was inhibited. In permeabilized monolayer experiments, both terbutaline and amiloride produced sustained decreases in current. The current-voltage relationship of the terbutaline-sensitive current had a reversal potential of28 mV. Increasing Cl concentration in thebasolateral solution shifted the reversal potential to more depolarizedvoltages. These results were consistent with the existence of aterbutaline-activated Cl conductance in the apicalmembrane. Terbutaline did not increase the amiloride-sensitiveNa⁺ conductance. We conclude that -adrenergicstimulation of adult alveolar epithelial cells results in an increasein apical Cl permeability and thatamiloride-sensitive Na⁺ channels are not directly affectedby this stimulation.