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Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton,
New Jersey 08543
[3H]P1075 binding to membrane preparations of rabbit
skeletal muscle were observed in the presence of nucleotide
triphosphates or diphosphates but not AMP, cAMP, adenosine,
tripolyphosphate, or pyrophosphate. Nonhydrolyzable or poorly
hydrolyzable ATP analogs inhibited MgATP-supported binding. The
EC50 value for MgATP-supported binding (0.4 mM)
was decreased ~10-fold in the presence of an ATP-regenerating system,
and significant metabolism by membrane nucleotidases was confirmed by
high performance liquid chromatographic analysis.
[3H]P1075 bound to skeletal muscle with a
Kd value of 37 ± 3 nM and a Bmax value of 280 ± 14 fmol/mg of protein. [3H]P1075 binding to
subcellular fractions was highest in membranes enriched in T tubules.
Specific binding was reversible, trypsin-sensitive, maximal at pH 8, and stereoselective for the
(3S,4R)-enantiomer of cromakalim.
Potassium channel openers exhibited a rank order of potency of
P1075 > pinacidil > levcromakalim = BMS-180448 > nicorandil > diazoxide = BRL 38226. Fluorescein analogs
(ethyleosin, phloxine B, and rose bengal) were relatively potent
inhibitors of binding (Ki = 200-300
nM). The potassium channel openers cromakalim and
BMS-180448 were competitive inhibitors of [3H]P1075
binding. In contrast, rose bengal and the ATP-regulated potassium
channel antagonist glyburide increased the rate of
[3H]P1075 dissociation in a manner consistent with
noncompetitive interaction.
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