RESUMEN
BACKGROUND: The design, medicinal chemistry, pharmacokinetics and development of the highly selective α2-adrenoceptor antagonist fluparoxan are reviewed. METHOD: The drug's activity and selectivity in vitro, its efficacy in animals and its excellent oral pharmacokinetics and central α2-adrenoceptor antagonist activity in man, are evaluated as well as its ability to increase extracellular levels of noradrenaline, dopamine and acetylcholine in vivo. CONCLUSION: Furthermore, its potential for the treatment of central neurodegenerative diseases is highlighted, in particular its improvement of cognitive dysfunction in schizophrenia and in models of Alzheimer's disease.
Asunto(s)
Adrenérgicos/farmacología , Sistema Nervioso Central/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Descubrimiento de Drogas , Enfermedades Neurodegenerativas/tratamiento farmacológico , Piperoxano/análogos & derivados , Pirroles/farmacología , Adrenérgicos/síntesis química , Adrenérgicos/química , Animales , Sistema Nervioso Central/patología , Disfunción Cognitiva/patología , Humanos , Enfermedades Neurodegenerativas/patología , Piperoxano/síntesis química , Piperoxano/química , Piperoxano/farmacología , Pirroles/síntesis química , Pirroles/químicaRESUMEN
A novel series of tetrahydrobenzodioxinopyrroles has been identified as potent and selective alpha 2-adrenoceptor antagonists. Convergent syntheses have been developed that allowed the preparation of analogues and their enantiomers. A compound of particular interest is the 5-fluoro substituted analogue (fluparoxan).
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Antagonistas Adrenérgicos alfa/química , Animales , Técnicas In Vitro , Masculino , Ratones , Estructura Molecular , Piperoxano/análogos & derivados , Piperoxano/síntesis química , Piperoxano/química , Piperoxano/farmacología , Pirroles/química , Ratas , EstereoisomerismoRESUMEN
The synthesis and in vitro alpha- and beta-adrenergic blocking potency of 1-[1-(2-benzodiaxanylmethyl)-4-piperidyl]amino-3-(1-naphthoxy-2-pr opanol (I) are described. Thus, N-benzyl-4piperidone was protected and debenzylated to the carbamate (V), which upon alkaline hydrolysis and acylation gave benzodioxanic amide (IX). Reduction of the amide group, deprotection of the ketone function of (X), and reductive amination gave the 4-aminopiperidine (XIII), which was finally condensed with the appropriate epoxide to yield the aminopropanol (I). Compound (I) is formally derived from a combination of piperoxan (II) and propranolol (III), and was approximately 10 times less potent than each one of these drugs, as an alpha- and beta-adrenergic blocker respectively.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos beta/síntesis química , Piperoxano/análogos & derivados , Propranolol/análogos & derivados , Animales , Aorta Torácica/efectos de los fármacos , Fenómenos Químicos , Química , Femenino , Cobayas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Piperoxano/síntesis química , Propranolol/síntesis química , Ratas , Tráquea/efectos de los fármacos , Conducto Deferente/efectos de los fármacosRESUMEN
Three piperoxan analogues, derived from the opening of the benzodioxane ring and/or replacement of the oxygen atom with the less polar sulfur, were synthesized. The decrease of the alpha-blocking activity found for these compounds showed that the binding site of benzodioxane-like compounds does not accept the substitution with less polar groups.