ABSTRACT
On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators.
Subject(s)
Benzothiadiazines/pharmacology , Diazoxide/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Receptors, AMPA/agonists , Animals , Benzothiadiazines/chemistry , Cells, Cultured , Cognition/drug effects , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Diazoxide/chemistry , Drug Design , Excitatory Amino Acid Agonists/chemical synthesis , Excitatory Amino Acid Agonists/chemistry , Excitatory Postsynaptic Potentials/drug effects , Female , Hippocampus/drug effects , Hippocampus/physiology , Long-Term Potentiation/drug effects , Membrane Potentials/drug effects , Mice , Models, Chemical , Molecular Structure , Norepinephrine/metabolism , Oocytes/drug effects , Oocytes/metabolism , Rats , Receptors, AMPA/metabolism , Thiadiazines/chemical synthesis , Thiadiazines/chemistry , Thiadiazines/pharmacology , Thiophenes/chemistry , Xenopus laevis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacologyABSTRACT
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.
