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

Russell, Keith; Brown, Frederick J.; Warwick, Paul J.; Forst, Janet M.; Grant, T.; Howe, Burton B.; Kau, Sen T.; Li, J.H.; McLaren, Frances M.; Shapiro, Howard S.; Trivedi, Shephali

doi:10.1016/s0960-894x(01)80752-6

Cited by 11 publications

(3 citation statements)

References 6 publications

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“…However, such a method was not deemed suitable in the present study since blood flow across the stenosis is dependent on blood pressure and, given the potent hypotensive effects of ZM260384 (Russell et al 1993), it was suspected that blood pressure post-ZM260384 would be insufficient to support a basal level of hindlimb perfusion. Instead, it was decided to perfuse the hindlimb by roller pump.…”

Section: Discussion Of Methodsmentioning

confidence: 92%

“…The aim of the present study was to determine whether the potassium channel opener ZM260384 (Russell et al 1993) could accelerate the decline in function in skeletal muscle during restricted flow in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In an isolated skeletal muscle preparation, this agent demonstrates a similar profile of activity to standard potassium channel opening agents and inhibits electrically induced skeletal muscle contractions by a glibenclamide-sensitive mechanism (Wickenden et al 1996). In vivo, ZM260384 is a hypotensive agent (Russell et al 1993). Collectively, the profile of activity of ZM260384 is entirely consistent with potassium channel opening as the principal mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

Wickenden¹,

Brooks²,

Kelly³

et al. 1997

Experimental Physiology

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SUMMARYThe aim of the present experiment was to determine whether the potassium channel opener 2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine-N-oxide (ZM260384) was capable of' accelerating the decline in skeletal muscle function during restricted blood flow in vivo. Cats (3.0-4.5 kg body weight) were anaesthetized with alphaxalone-alphadalone and breathed spontaneously following tracheotomy. Isometric tension was measured in the extensor digitorum longus-anterior tibialis (EDL-TA) muscle group. Ischaemia was induced by perfusing the hindlimb with the animal's own blood at a rate of 12 5 ml min' using a roller pump and stimulating the common peroneal nerve to induce repetitive submaximal tetanic contractions in the EDL-TA. The number of stimulation voltage increments required each minute to maintain a constant level of submaximal mechanical output and the time to exhaustion were used as indices of the rate of tension decline. The rate of tension decline in the ischaemic EDL-TA in the presence of ZM260384 at 3 mg kg-', a maximally hypotensive dose predicted to be within the dose range required to exert direct effects on skeletal muscle, was measured and compared with the rate of tension decline in the presence of ZM260384 at 0 03 mg kg-', also a maximally hypotensive dose but below the predicted dose range for skeletal muscle effects. The number of voltage increments per minute was 1.93 + 0 07 and 1-48 + 0 14 (P < 0 05) in the presence of 3 and 0-03 mg kg ZM260384, respectively. Time to exhaustion was 17 5 + 4-2 and 7 2 + 0-8 min (P < 0-05) in the presence of 3 and 003 mg kg-IZM260384, respectively. Given that there was no difference between these two groups in any haemodynamic variable measured, the results of the present study suggest that ZM260384 (3 mg kg ') increases the rate of isometric force loss in ischaemic skeletal muscle in vivo.

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Section: Discussion Of Methodsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

Wickenden¹,

Brooks²,

Kelly³

et al. 1997

Experimental Physiology

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ChemInform Abstract: A Highly Potent Series of Fluoroalkyl Benzoxazine Pyridine N‐Oxide Potassium Channel Openers, e.g. (I).

et al. 1994

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K_ATP channel openers: Structure‐activity relationships and therapeutic potential

Mannhold

2003

Medicinal Research Reviews

157

111

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ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K(ATP) channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K(ATP) channels. Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols.

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

Cited by 11 publications

References 6 publications

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

ChemInform Abstract: A Highly Potent Series of Fluoroalkyl Benzoxazine Pyridine N‐Oxide Potassium Channel Openers, e.g. (I).

K_ATP channel openers: Structure‐activity relationships and therapeutic potential

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

Cited by 11 publications

References 6 publications

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

ChemInform Abstract: A Highly Potent Series of Fluoroalkyl Benzoxazine Pyridine N‐Oxide Potassium Channel Openers, e.g. (I).

KATP channel openers: Structure‐activity relationships and therapeutic potential

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K_ATP channel openers: Structure‐activity relationships and therapeutic potential