RESUMEN
First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Colinérgicos/farmacología , Colinérgicos/uso terapéutico , Diseño de Fármacos , Industria Farmacéutica , Quimioterapia/tendencias , Humanos , Estrés OxidativoRESUMEN
Potassium channels play a crucial role in controlling the cell membrane potential. Among the different varieties of K(+) channels, the ATP-sensitive potassium channels (K(ATP) channels) have been characterized in numerous cell types, such as skeletal and smooth muscle cells, endocrine cells, cardiac cells and central neurons. Several molecules are known to activate K(ATP) channels and have been named "potassium channel openers" (PCOs). Such compounds may have a wide therapeutic potential and a few drugs are currently used as antihypertensive agents. Different chemical series of PCOs have been explored. This heterogeneous group of organic compounds comprises the benzopyran series including potent vasorelaxant drugs, such as cromakalim. The latter compound, a typical example of potassium channel opener, exerts its biological effect by activating K(ATP) channels. This review presents recent developments in the chemistry of cromakalim analoges and reports chemical aspects governing their potency and tissue selectivity.
Asunto(s)
Cromakalim/análogos & derivados , Canales de Potasio/agonistas , Vasodilatadores/farmacología , Animales , Bronquios/efectos de los fármacos , Cromakalim/farmacología , Humanos , Activación del Canal Iónico/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacosRESUMEN
A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.
Asunto(s)
Óxidos S-Cíclicos/síntesis química , Diazóxido/química , Músculo Liso Vascular/efectos de los fármacos , Pinacidilo/química , Canales de Potasio/efectos de los fármacos , Tiadiazinas/síntesis química , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/fisiología , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Diseño de Fármacos , Femenino , Cobayas , Íleon/citología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/citología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiadiazinas/química , Tiadiazinas/farmacología , Contracción Uterina/efectos de los fármacos , Vasodilatadores/síntesis química , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.