Zeneca ZD6169 and Its Analogs from a Novel Series of Anilide Tertiary Carbinols: In vitro K_ATP Channel Opening Activity in Bladder Detrusor

Abstract

The potassium (K⁺) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoin-hibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K⁺ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 ± 0.22 to 223 ± 37 µmol/l. This result suggests that ZD6169 may act as a K⁺ channel opener. Similar to the prototypic ATP-sensitive K⁺ (K_ATP) channel opener cromakalim, the K⁺ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KC1. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 µmol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 ± 1.2 mV and increased the whole cell K_Atp current in isolated guinea pig smooth muscle cells by 34.9 ± 7.9 pA. This is comparable to the increase of 26.8 ± 5.0 pA obtained with 10 µmol/l of lemakalim, the active enantiomer of cromakalim. The K⁺ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the K_Atp channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K⁺ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K⁺ channel openers that activate K_ATP channels in vitro to relax bladder detrusors.

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

“…Antimuscarinic agents, which impair UBSM contraction, are used to treat urinary incontinence but have limited effectiveness and undesirable side effects. More recently, potassium channel opening drugs have been explored as therapeutic agents for urinary incontinence (2)(3)(4)(5)(6).…”

Small-conductance, Ca2+-activated K+ channel 2 is the key functional component of SK channels in mouse urinary bladder

“…This dampens neuronal firing and reduces bladder stimulation (22, 31). Activation of UBSM ATP-sensitive K ϩ channels hyperpolarizes the resting UBSM membrane potential and reduces the action potential frequency, resulting in a decreased contractility (3,21,30) and an increased bladder capacity (27). Elimination of large-conductance, Ca 2ϩ -activated K ϩ channels, which facilitate UBSM action potential repolarization, results in overactive detrusor and incontinence (11,25,35).…”

Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine KATP Channel Activator

“…This profile of ZM244085 is similar to that of the prototypic ATP-sensitive Kf(KATP) channel activator cromakalim in the urinary bladder (17), but contrasts that of nifedipine or nimodipine, which exhibit much more potent relaxation activity in tissues highly depolarized with 80 mM KCl (16).…”