Interaction of a novel dihydropyridine K⁺ channel opener, A‐312110, with recombinant sulphonylurea receptors and K_ATP channels: comparison with the cyanoguanidine P1075

Abstract

1 ATP-sensitive K þ channels (K ATP channels) are composed of pore-forming subunits (Kir6.x) and of regulatory subunits, the sulphonylurea receptors (SURx). Synthetic openers of K ATP channels form a chemically heterogeneous class of compounds that are of interest in several therapeutic areas. We have investigated the interaction of a novel dihydropyridine opener, A-312110 ((9R)-9-(4-fluoro-3-iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano [3,4-b]thieno [2,3-e]pyridin-8(7H)-one-1,1-dioxide), with SURs and Kir6/SUR channels in comparison to the cyanoguanidine opener P1075. 2 In the presence of 1 mM MgATP, A-312110 bound to SUR2A (the SUR in cardiac and skeletal muscle) and to SUR2B (smooth muscle) with K i values of 14 and 18 nM; the corresponding values for P1075 were 16 and 9 nM, respectively. Decreasing the MgATP concentration reduced the affinity of A312110 binding to SUR2A significantly more than that to SUR2B; for P1075, the converse was true. At SUR1 (pancreatic b-cell), both openers showed little binding up to 100 mM. 3 In the presence of MgATP, both openers inhibited [ 3 H]glibenclamide binding to the SUR2 subtypes in a biphasic manner. In the absence of MgATP, the high-affinity component of the inhibition curves was absent. 4 In inside-out patches, the two openers activated the Kir6.2/SUR2A and Kir6.2/SUR2B channels with similar potency (B50 nM). Both were almost 2 Â more efficacious in opening the Kir6.2/SUR2B than the Kir6.2/SUR2A channel. 5 The results show that the novel dihydropyridine A-312110 is a potent K ATP channel opener with binding and channel-opening properties similar to those of P1075.

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury

“…A KCO P-1075 binds with high affinity to cardiac KATP channel but not to pancreatic β-cell KATP channel [56,57]. We demonstrated that the selective mitoKATP These data demonstrated the fundamental possibility of creating the cardioselective mitoKATP channel opener without negative hemodynamic and proarrhythmic effects.…”

“…KCOs are categorized as follows for their ability to induce relaxation of coronary arteries: rilmakalim > P1075 > bimakalim > > levcromakalim > aprikalim > minoxidil > (−)‐pinacidil > (+)‐pinacidil > nicorandil > diazoxide [18]. A KCO P‐1075 binds with high affinity to cardiac KATP channel but not to pancreatic β‐cell KATP channel [56, 57]. We demonstrated that the selective mitoKATP channel opener BMS‐191095 reduced infarct size in dogs with CAO (90 min) and reperfusion (5 h) without effects on hemodynamics [58].…”

The mutation Y1206S increases the affinity of the sulphonylurea receptor SUR2A for glibenclamide and enhances the effects of coexpression with Kir6.2

“…Owing to high nonspecific binding, [ 3 H]GBC binding experiments were not possible in the presence of MgATP nor in intact cells. The K D value determined here for P1075 binding to SUR2A in the presence of MgATP (Table 3) is the same as that determined earlier (Hambrock et al ., 1999) and is 2–5 times lower than that of SUR2B (Hambrock et al ., 1999; Felsch et al ., 2004). The mutation Y1206S increased the affinity of SUR2A for GBC ∼5 times (Table 1) and enhanced the potency of GBC to inhibit [ 3 H]P1075 binding ∼4 × (Table 3) but it did not affect the affinity of SUR2A for openers (Table 3).…”

In vitro and in vivo characterization of a novel naphthylamide ATP‐sensitive K+ channel opener, A‐151892

“…Subsequently, compounds such as the tertiary carbinol ZD6169 and aryl squarate WAY 133537 with modestly improved in vivo selectivity for the urinary bladder relative to benzopyrans such as cromakalim and celikalim have emerged ( Howe et al ., 1995 ; Wojdan et al ., 1999 ). More recently, compounds belonging to the 1.4‐dihydropyridine class including A‐312110 and A‐278637 have been synthesized and characterized ( Gopalakrishnan et al ., 2002 ; Davis‐Taber et al ., 2003 , Felsch et al ., 2004 ). In particular, A‐278637 was demonstrated to possess enhanced potencies for suppression of unstable bladder contractions vs mean arterial blood pressure effects in an obstructed pig model relative to earlier generation compounds ( Brune et al ., 2002 ).…”