title: 1,4-Benzothiazine ATP-sensitive potassium channel openers: modifications at the C-2 and C-6 positions.
abstract: ATP-sensitive potassium (KATP) channels play a prominent role in controlling cardiovascular function. In this paper, a novel series of 4-(1-oxo-2-cyclopentenyl)-1,4-benzothiazine derivatives modified at the C-2, and C-6 positions were synthesized as openers of vascular KATP channels. Most of the tested compounds evoked vasorelaxing effects on rat aortic rings and membrane hyperpolarization in human vascular smooth muscle cells, with potency similar or superior to that of the reference levcromakalim (LCRK). The selective KATP blocker glibenclamide antagonized the above vascular effects, confirming that KATP channels are closely involved in the mechanism of action. The experimental results confirmed the 1,4-benzothiazine nucleus as an optimal scaffold for activators of vascular KATP channels; moreover, the high level of potency exhibited by the 6-acetyl substituted benzothiazine 8, along with the lack of any significant interference with insulin secretion from pancreatic β-cells, paves the way to further develop a new series of potent activators of vascular KATP channels.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Paola
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Michela
authors.initials: M
authors.lastname: Novelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Masiello
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003517:Cyclopentanes; D007328:Insulin; D054086:KATP Channels; D013843:Thiazines; D014665:Vasodilator Agents