Structural nucleotide analogs are potent activators/inhibitors of pancreatic β cell KATP channels: an emerging mechanism supporting their use as antidiabetic drugs.
The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic β cell ATP-sensitive K+ (KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic β cell KATP channel and the Kir6.2ΔC36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by intraperitoneal glucose tolerance test and on fasting glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP (IC₅₀ = 10.1 × 10⁻⁹ M) and Kir6.2ΔC36 (IC₅₀ = 9.6 × 10⁻⁹ M) channels, which induced depolarization. In contrast, the 2-phenyl analog was a potent opener (drug concentration needed to enhance the current by 50% = 0.04 × 10⁻⁹ M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl > 2-benzyl > 2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2-10 mg/kg) and 2-phenyl analogs (2-30 mg/kg) reduced and enhanced the glucose areas under the curves, respectively, after glucose loading in mice. These compounds did not affect the fasting glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which confer the KATP channel blocking action with glucose-lowering effects and the opening action with increased glucose levels, respectively. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel antidiabetic drugs.
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Via Orabona No. 4, I-70126 Bari, Italy. dtricarico@farmbiol.uniba.it
Domenico
D
Tricarico
Jean-François
JF
Rolland
Gianluigi
G
Cannone
Antonietta
A
Mele
Valentina
V
Cippone
Antonio
A
Laghezza
Giuseppe
G
Carbonara
Giuseppe
G
Fracchiolla
Paolo
P
Tortorella
Fulvio
F
Loiodice
Diana
D
Conte Camerino
D000818:Animals; D019540:Area Under Curve; D048588:Benzoxazines / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D005215:Fasting / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019810:Sodium Azide / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
D048588:Benzoxazines; D001786:Blood Glucose; D005947:Glucose; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D019810:Sodium Azide; D014044:Tolbutamide; D000099161:Kcnj11 Channel