Keith Russell

Chapter 9. Potassium Channel Openers

Publisher Summary The science of potassium channels is in a very exciting phase. Potassium (K + ) channels play a central role in the regulation of cellular excitability. They are involved in setting the membrane potential, in addition to controlling the frequency and shape of action potentials. New K + channels are being cloned and knowledge of structure–function of K + channels is rapidly increasing. Structurally diverse series of potassium channel openers/activators (PCOs) continue to be discovered. Activation or opening of potassium channels by organic molecules have been largely confined to the adenosine triphosphate (ATP)-sensitive (K ATP ) and large conductance calcium (Ca 2+ )-activated (BK ca ) potassium channels. The cellular pharmacology of PCOs in vascular smooth muscle, their mechanism of action, and their clinical potential are well studied. PCOs are also being studied as novel therapeutics for the treatment of pain. The PCOs diazoxide, minoxidil, and levcromakalim produced anti-nociception in the rat tail flick model. This effect is antagonized by glyburide supporting K ATP opening as the mode of action. The anti-nociception induced by morphine (a popioid agonist) is markedly potentiated by cromakalim. These findings suggest that the activation of central K ATP channels may play an important role in the modulation of the anti-nociception induced by μ agonists.

ZENECA ZD6169 and its analogs from a novel series of anilide tertiary carbinols: in vitro KATP channel opening activity in bladder detrusor

The potassium (K+) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoinhibitory 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 +/- 0.22 223 +/- 37 mumol/l. This result suggests that ZD6169 may act as a K+ channel opener. Similar to the prototypic ATP-sensitive K+ (KATP) 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 KCl. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 mumol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 +/- 1.2 mV and increased the whole cell KATP 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 mumol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the KATP 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 KATP channels in vitro to relax bladder detrusors.

K-Channel Opening Activity of ZD6169 and Its Analogs: Effect on 86Rb Efflux and 3H-P1075 Binding in Bladder Smooth Muscle

Zeneca ZD6169, (S)-N-(4-benzoylphenyl)-3,3,3-trifluoro- 2-hydroxy-2-methylpropionamide, is a novel compound which relaxes urinary bladder smooth muscle in vitro. The effect of ZD6169 and two of its analogs on 86Rb efflux and 3H-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. ZD6169 concentration dependently increased the rate of 86Rb efflux from guinea pig bladder strips. 86Rb efflux evoked by ZD6169 and its analogs was blocked by glibenclamide (30 muM) but not by charybdotoxin, apamin or alpha-dendrotoxin, suggesting that this compound activates KATP channels in guinea pig bladder. In addition, interaction of ZD6169 with KATP channels was also confirmed in human bladder smooth muscle cells. Specific binding of 3H-P1075, a potent opener of KATP channels, to guinea pig urinary bladder strips was observed. 3H-P1075 binding was inhibited by known KATP openers. ZD6169 inhibited binding of 3H-P1075 to urinary bladder strips like other structurally different KATP openers, e.g. cromakalim and pinacidil. Potencies for inhibition of 3H-P1075 binding by ZD6169 and other potassium channel openers correlate well with potencies for increase in 86Rb efflux and bladder muscle relaxation studies. It is concluded that Zeneca ZD6169 is a potassium channel opener which activates ATP-sensitive K-channels in guinea pig urinary bladder strips as well as in human bladder cells. Furthermore, binding studies suggest that the effects of ZD6169 and its analogs are mediated by binding to the site labeled by 3H-P1075 in guinea pig bladder strips.

Anilide tertiary carbinols: A new structural class of potent potassium channel openers

Abstract A new structural class of anilide tertiary carbinol potassium channel openers (PCOs) is described.

The effects of pharmacological modulation of KATP on the guinea-pig isolated diaphragm

The purpose of the present study was to investigate the functional consequences of KATP modulation in the normal and the metabolically inhibited guinea-pig isolated diaphragm using the K+ channel openers cromakalim, pinacidil, RP49356 (N-methyl-2-(3-pyridil)-tetrahydrothiopyran-2-carbothiami de-1-oxide) and ZM260384 (2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine -4-yl)pyridine-N-oxide) and the K+ channel inhibitors glibenclamide, phentolamine and ciclazindol. All K+ channel openers accelerated the decline in function induced by intermittent tetanic contractions following metabolic inhibition and delayed the development of contracture. Cromakalim also improved the recovery of twitch tension following 10 min intermittent tetanic stimulation in the hypoxic guinea-pig diaphragm preparation. Of the K+ channel inhibitors tested, only ciclazindol, at the highest concentration tested (10 microM), significantly delayed the decline in tetanic tension following metabolic inhibition in the guinea-pig isolated diaphragm. None of the inhibitors significantly accelerated the development of contracture. All inhibitors however, antagonised the actions of the K+ channel opener, cromakalim. The results indicate that opening of KATP can accelerate the decline in function following metabolic inhibition in the guinea-pig isolated diaphragm. In the absence of K+ channel openers however, KATP does not appear to contribute to this decline under the conditions of the present study.

A highly potent series of fluoroalkyl benzoxazine pyridine-N-oxide potassium channel openers

Abstract A new structural class of fluoroalkyl benzoxazine pyridine-N-oxide potassium channel openers (PCOs) is described.

Crystal receptor models in medicinal chemistry: Application to the generation of highly potent potassium channel openers

Abstract The cavity produced by removing one molecule of the potassium channel opener (PCO) cromakalim from its crystal lattice, contains shape and electrostatic information that has been exploited as a tool in drug design.