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

Tricarico, Domenico; Mele, Antonietta; Camerino, Giulia Maria; Laghezza, Antonio; Carbonara, Giuseppe; Fracchiolla, Giuseppe; Tortorella, Paolo; Loiodice, Fulvio; Camerino, Diana Conte

doi:10.1124/mol.108.046615

Cited by 11 publications

(17 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A conformational analysis showed that the planar area of the 2H-1,4-benzoxazines overlaps that of the adenine nucleotide tri-and diphosphates. The electronic distribution profile of this area is also similar to that of the adenine nucleotides, which were reached by electrons; this result suggests that these compounds share a common ATP/ADP interaction interface on the receptor sites (Tricarico et al, 2008). No data are available regarding the effects or possible dual actions of these nucleotide analogs on the pancreatic ␤ cell KATP channel or glucose disposal in normal mice.…”

Section: Introductionmentioning

confidence: 82%

“…A biphasic behavior was observed in the glucose disposal curves that were determined in vivo after the administration of increasing doses of the 2-nhexyl analog; these data can be explained by accounting for the opposite in vitro effects of this compound on pancreatic ␤ cells and skeletal muscle KATP channels (Fig. 9) (Tricarico et al, 2008).…”

Section: Downloaded Frommentioning

confidence: 98%

“…The experiments are illustrated by the traces, means, or representative results that were obtained from at least three different cultures. The concentrationresponse data were fitted by an equation that described the interaction of the ligand with one inhibitory site, as in the case of the 2-hexyl analog data, or by the sum of two equations that described the interaction of the ligand with two sites that exerted opposite actions, as in the case of the 2-cyclic analog data (Tricarico et al, 2008). The stimulatory component can be described by the following term:…”

Section: Methodsmentioning

confidence: 99%

“…The drug experiments were performed using the patch-clamp methodology in the voltage-clamp mode (perforated whole-cell, conventional whole-cell, and inside-out configurations), and the current-clamp mode was performed using Clampex software (Molecular Devices, Sunnyvale, CA) (Rolland et al, 2006;Tricarico et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…In the presence of ATP, these molecules display KCO activity, whereas in the absence of the nucleotide they display a blocking action (Tricarico et al, 2003(Tricarico et al, , 2008. These compounds have structural similarities with ATP and ADP molecules.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

Tricarico

Rolland²,

Cannone³

et al. 2012

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

View full text Add to dashboard Cite

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic ␤ cell ATP-sensitive K ϩ (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 ␤ cell KATP channel and the Kir6.2⌬C36 subunit were investigated using a patchclamp 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 (IC 50 ϭ 10.1 ϫ 10 Ϫ9 M) and Kir6.2⌬C36 (IC 50 ϭ 9.6 ϫ 10 Ϫ9 M) channels, which induced depolarization. In contrast, the 2-phenyl analog was a potent opener (drug concentration needed to enhance the current by 50% ϭ 0.04 ϫ 10 Ϫ9 M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl Ͼ 2-benzyl Ͼ 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.

show abstract

Section: Introductionmentioning

confidence: 82%

Section: Downloaded Frommentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

Tricarico

Rolland²,

Cannone³

et al. 2012

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

Employment of the TiCl4–Anisole–Pyridine System in the Condensation of Amides with Aromatic Amines

Chernyak

Ponomaryov

Varacheva

et al. 2014

Chem Heterocycl Comp

View full text Add to dashboard Cite

Amidine fragment (-N-C=N-) is frequently present in the structures of biologically active compounds and active pharmaceutical ingridients [1][2][3][4], since exhibits the properties of pharmacophoric group. Possessing four bonds, which might be linked with the diverse substituents, amidine fragment can be a part of linear structures or nitrogen-containing heterocycles. Additionally, the fragment may serve as a bridgehead in bicyclic molecules, for example, in 1, 8-diazobycyclo[5.4.0]undec-7-ene, employed in the organic synthesis [5], and also in the antipsychotic drug, risperidone [3].One of the most common methods for the synthesis of amidines is the reaction of amides with amines in the presence of condensing agents (e.g., POCl 3 , SOCl 2 ). Titanium(IV) chloride is also used as the condensation agent for the preparation of amidines [6], usually in the form of complexes with the aromatic ethers, such as anisole (PhOMe) [1], that makes the reagent much easier to handle. However, our literature search uncovered that titanium(IV) chloride is primarily being used in the reactions of amides with aliphatic amines, moreover the amine utilized in large excess. Employment of TiCl 4 in reactions of amides with aromatic amines is limited to few cases [7,8].Recently [9] we were able to employ the TiCl 4 -PhOMe complex as a condensation agent in the synthesis of anticancer drug (for non-small cell lung cancer), erlotinib (2а), starting from 6,7-bis(2-methoxyethoxy)quinazolin-4(3Н)-оne (1). The majority of the patented methods for the synthesis of erlotinib involves the preparation of the activated intermediate (e.g., 4-chloroquinazoline derivative [10]) from amide 1, the reaction of which with 3-ethynylaniline yields the target compound 2a. In contrast, using the TiCl 4 -PhOMe complex in polar aprotic solvents (dioxane and diglyme) allowed us to obtain erlotinib (2a) with satisfactory yields in one-pot condensation of amide 1 with 3-ethynylaniline. However, in the course of further development of this method we revealed several drawbacks: poor reproducibility of results (conversion of the starting amide 1 and the yield of product), presumably due to the high sensitivity of a condensing agent to presence of moisture. Adding further amounts of the TiCl 4 -PhOMe complex to the reaction mixture in order to increase the conversion of amide 1 lead to resinification of the reaction mixture, which was presumably due to the instability of triple bond of 3-ethynylaniline and the product 2a in acidic medium.

show abstract

An efficient synthesis of the optically active isomers of 2H-1,4-benzoxazine derivatives, novel KATP channel modulators

Piemontese

Laghezza

Fracchiolla

et al. 2013

Tetrahedron: Asymmetry

View full text Add to dashboard Cite

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

Cited by 11 publications

References 27 publications

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

Employment of the TiCl4–Anisole–Pyridine System in the Condensation of Amides with Aromatic Amines

An efficient synthesis of the optically active isomers of 2H-1,4-benzoxazine derivatives, novel KATP channel modulators

Contact Info

Product

Resources

About