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.

Molecular Pharmacology
D TricaricoDiana Conte Camerino

Abstract

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 (DE(50) = 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 > or =2-cyclohexylmethyl >2-isopropyl = 2-n-butyl > or = 2-phenyl > or = 2-benzyl = 2-isobutyl analogs. In the absence of ATP, the 2-phenyl analog was the most potent inhibitor (IC(50) = 2.5 x 10(-11) M); the rank order of efficacy of the blockers was 2-phenyl > or = 2-n-hexyl > 2-n-butyl > 2-cyclohex...Continue Reading

References

Nov 1, 1992·Pflügers Archiv : European journal of physiology·B Allard, M Lazdunski
Apr 1, 1992·Pharmacology & Toxicology·K E Andersson
Sep 4, 1990·European Journal of Pharmacology·S QuasthoffP Grafe
Mar 1, 1995·Journal of Clinical Pharmacology·T P LinksW D Reitsma
May 1, 1994·Trends in Pharmacological Sciences·G E Rovati, S Nicosia
Oct 12, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·M BienengraeberA Terzic
May 29, 2003·British Journal of Pharmacology·Domenico TricaricoDiana Conte Camerino
May 29, 2003·British Journal of Pharmacology·Ulrich RussUlrich Quast
Jan 6, 2004·Medicinal Research Reviews·Raimund Mannhold
Feb 10, 2004·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Domenico TricaricoDiana Conte Camerino
Mar 12, 2005·The Journal of Biological Chemistry·Tong LuHon-Chi Lee
May 25, 2005·Journal of Molecular and Cellular Cardiology·Alexey E AlekseevAndre Terzic
Jun 15, 2005·Journal of Molecular and Cellular Cardiology·A Jahangir, Andre Terzic
Jan 19, 2006·Proceedings of the National Academy of Sciences of the United States of America·Domenico TricaricoDiana Conte Camerino
Jun 22, 2006·Current Topics in Medicinal Chemistry·Violetta CecchettiStefano Sabatini
Mar 31, 2007·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Diana Conte CamerinoJean-François Desaphy

❮ Previous
Next ❯

Citations

Jun 1, 2016·Frontiers in Pharmacology·Paola ImbriciDiana Conte
Oct 27, 2011·The Journal of Pharmacology and Experimental Therapeutics·Domenico TricaricoDiana Conte Camerino
Jan 20, 2021·CNS & Neurological Disorders Drug Targets·Fatima MaqoudDomenico Tricarico

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.