N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides:  KATP Potassium Channel Openers. Modifications on the Western Region

Ohnmacht, Cyrus J.; Russell, Keith; Empfield, James R.; Frank, Cathy A.; Gibson, K. H.; Mayhugh, Daniel R.; McLaren, Frances M.; Shapiro, Howard S.; Brown, Frederick J.; Trainor, Diane A.; Ceccarelli, C.; Lin, Margaret M.; Masek, Brian B.; Forst, Janet M.; Harris, Robert; Hulsizer, James M.; Lewis, Joseph J.; Silverman, Stuart M.; Smith, Reed W.; Warwick, Paul J.; Kau, Sen T.; Chun, Alexa L.; Grant, T.; Howe, Burton B.; Li, Jack H.; Trivedi, Shephali; Halterman, Tracy J.; Yochim, Christopher; Dyroff, Martin C.; Neilson, Kathleen L.

doi:10.1021/jm9700373

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“…Interaction ofZM 249I38 andZM 259928 with Ka Tp Channels ZM249138 and ZM259928, although structurally different from ZD6169, have also been shown to open K-channels in guinea pig bladder smooth muscle [15,22]. Like ZD6169, ZM249138, the S(-)-enantiomer, was much more potent than its respective R(+)-enantiomer, ZM249137, in evoking 86Rb efflux (data not shown).…”

Section: Interaction Oj'zd6169 With Katp Channelsmentioning

confidence: 97%

“…Currently, several structurally different groups of PCOs are known which have been reported to exert their relaxant activity in vascular and nonvascular smooth muscle [10][11][12][13][14] by opening ATP-sensitive K-channels (KAtp)-Recently we have discovered novel tertiary carbinols, especially ZD6169 ( fig. 1), which has been found to open K-channels in guinea pig uri nary bladder smooth muscle [15,16]. The present study was undertaken to provide evi dence for the PCO activity of ZD6169 and two of its analogs in guinea pig urinary blad der strips.…”

mentioning

confidence: 99%

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

Trivedi

Sl²,

Potter-Lee³

et al. 1995

Pharmacology

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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 µM) but not by charybdotoxin, apamin or α-dendrotoxin, suggesting that this compound activates K_Atp channels in guinea pig bladder. In addition, interaction of ZD6169 with K_Atp channels was also confirmed in human bladder smooth muscle cells. Specific binding of ³H-P1075, a potent opener of K_Atp channels, to guinea pig urinary bladder strips was observed. ³H-P1075 binding was inhibited by known K_Atp openers. ZD6169 inhibited binding of ³H-P1075 to urinary bladder strips like other structurally different K_ATp 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.