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Molecular Determinants for the Activating/Blocking Actions of the 2H-1,4-Benzoxazine Derivatives, a Class of Potassium Channel Modulators Targeting the Skeletal Muscle K_ATP Channels

Departments of Pharmacobiology (D.T., A.M., G.M.C., D.C.C.) and Medicinal Chemistry (A.L., G.C., G.F., P.T., F.L.), Faculty of Pharmacy, University of Bari, Bari, Italy

The 2H-1,4-benzoxazine derivatives are modulators of the skeletal muscle ATP-sensitive-K⁺ channels (K_ATP), activating it in the presence of ATP but inhibiting it in the absence of nucleotide. To investigate the molecular determinants for the activating/blocking actions of these compounds, novel molecules with different alkyl or aryl-alkyl substitutes at position 2 of the 1,4-benzoxazine ring were prepared. The effects of the lengthening of the alkyl chain and of branched substitutes, as well as of the introduction of aliphatic/aromatic rings on the activity of the molecules, were investigated on the skeletal muscle K_ATP channels of the rat, in excised-patch experiments, in the presence or absence of internal ATP (10^-4 M). In the presence of ATP, the 2-n-hexyl analog was the most potent activator (DE₅₀ = 1.08 x 10^-10 M), whereas the 2-phenylethyl was not effective. The rank order of efficacy of the openers was 2-n-hexyl 2-cyclohexylmethyl >2-isopropyl = 2-n-butyl 2-phenyl 2-benzyl = 2-isobutyl analogs. In the absence of ATP, the 2-phenyl analog was the most potent inhibitor (IC₅₀ = 2.5 x 10^-11 M); the rank order of efficacy of the blockers was 2-phenyl 2-n-hexyl > 2-n-butyl > 2-cyclohexylmethyl, whereas the 2-phenylethyl, 2-benzyl, and 2-isobutyl 1,4-benzoxazine analogs were not effective; the 2-isopropyl analog activated the K_ATP channel even in the absence of nucleotide. Therefore, distinct molecular determinants for the activating or blocking actions for these compounds can be found. For example, the replacement of the linear with the branched alkyl substitutes at the position 2 of the 1,4-benzoxazine nucleus determines the molecular switch from blockers to openers. These compounds were 100-fold more potent and effective as openers than other KCO against the muscle K_ATP channels.

Address correspondence to: Domenico Tricarico, Dept. of Pharmacobiology, Faculty of Pharmacy, via Orabona no. 4, Bari, Italy.