KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K⁺ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat

Abstract

Recent studies revealed that a new compound, KW-7158 [(2S)-(ϩ)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K ϩ currents at concentrations ranging from 50 nM to 1 M (20 -50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5-to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 M) or substance P (0.5 M) in phasic firing DRG neurons. Above 1 M, KW-7158 elicited a smaller enhancement of A-type K ϩ currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 M), which block noninactivating K ϩ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K ϩ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K ϩ currents in DRG neurons. Because A-type K ϩ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

Inhibition of the A-Type K+Channels of Dorsal Root Ganglion Neurons by the Long-Duration Anesthetic Butamben

“…Despite these differences, our data support the conclusion that Kv4 channels, either as homo-or heteromultimers, contribute to the rapidly inactivating A-type K ϩ current expressed in small DRG neurons. This conclusion is in good agreement with recent studies of DRG A-type K ϩ current (Fedulova et al, 1998;Sculptoreanu et al, 2004).…”

“…؉ Channels activate at voltages more depolarized than Ϫ60 mV, suggesting that the channels underlying this current may be active near the resting membrane potential (Ϫ55 mV) of these neurons (Christian et al, 1994;Wang et al, 1997;Sculptoreanu et al, 2004). The steady-state availability was determined from conditioning pulses between Ϫ120 and 0 mV and plotted versus voltage (Fig.…”

“…BAB is an inhibitor of the sodium, calcium, and delayed rectifier potassium currents of DRG neurons (Van den Berg et al, 1996;Beekwilder et al, 2003Beekwilder et al, , 2005, suggesting that the reduced electrical excitability of dorsal root pain fibers is the most likely mechanism of BAB anesthesia ( Van den Berg et al, 1995). Electrophysiological characterization of small DRG neurons has identified three broad classifications of voltage-gated K ϩ current expressed in these cells: a fast-inactivating ( Ϸ 10-ms) 4-aminopyridine (4-AP)-sensitive A-type current (I A ), a slowly inactivating ( Ϸ 100-ms) current, and a tetraethylammonium (TEA)-sensitive sustained current (Kostyuk et al, 1981;Christian et al, 1994;Gold et al, 1996;Safronov et al, 1996;Fedulova et al, 1998;Yoshimura and de Groat, 1999;Sculptoreanu et al, 2004).…”

Intrathecal Studies on Animal Pain Models

“…The expression of Kv3.4 and Kv4.3 in DRG neurons were found to be also decreased after spinal nerve ligation and intrathecal injections of antisense oligodeoxynucleotides against Kv3.4 or Kv4.3 in naïve rats could induce mechanical hypersensitivity (Chien et al, 2007). New compounds with A-type K + channel opening activity, such as KW-7158 (Sculptoreanu et al, 2004), may prove to be effective for the treatment of NINP. The Kv7 channel (also known as KCNQ) opener retigabine has been reported to be effective in sciatic chronic constrict injury (Blackburn-Munro & Jensen, 2003) and L5 spinal nerve ligation (Dost et al, 2004) pain models.…”

The Anti-overactive Bladder Activity of KW-7158 Is Mediated by Blocking Equilibrative Nucleoside Transporter-1

“…[1][2][3] Pharmacological studies using rats with xyleneirritated bladders, 4) cultured dorsal root ganglion (DRG) neurons, 5) and isolated bladder strips 6) suggest that KW-7158 has a unique mechanism of action, namely, it inhibits the contraction of the bladder smooth muscle by suppressing the activity of sensory nerves. This unique mode of action distinguishes KW-7158 as a drug candidate that may be free from the side effects caused by other anti-OAB drugs.…”