ABSTRACT
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.
Subject(s)
Adrenergic Agents/pharmacology , Central Nervous System/drug effects , Cognitive Dysfunction/drug therapy , Drug Discovery , Neurodegenerative Diseases/drug therapy , Piperoxan/analogs & derivatives , Pyrroles/pharmacology , Adrenergic Agents/chemical synthesis , Adrenergic Agents/chemistry , Animals , Central Nervous System/pathology , Cognitive Dysfunction/pathology , Humans , Neurodegenerative Diseases/pathology , Piperoxan/chemical synthesis , Piperoxan/chemistry , Piperoxan/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistryABSTRACT
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).
Subject(s)
Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Adrenergic alpha-Antagonists/chemistry , Animals , In Vitro Techniques , Male , Mice , Molecular Structure , Piperoxan/analogs & derivatives , Piperoxan/chemical synthesis , Piperoxan/chemistry , Piperoxan/pharmacology , Pyrroles/chemistry , Rats , StereoisomerismABSTRACT
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.
Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic beta-Antagonists/chemical synthesis , Piperoxan/analogs & derivatives , Propranolol/analogs & derivatives , Animals , Aorta, Thoracic/drug effects , Chemical Phenomena , Chemistry , Female , Guinea Pigs , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Piperoxan/chemical synthesis , Propranolol/chemical synthesis , Rats , Trachea/drug effects , Vas Deferens/drug effectsABSTRACT
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.
