SYNTHESIS AND BETA-BLOCKING ACTIVITY OF (R,S)-(E)-OXIMEETHERS OF 2,3-DIHYDRO-1,8-NAPHTHYRIDINE AND 2,3-DIHYDROTHIOPYRANO[2,3-B]PYRIDINE: IDENTIFICATION OF BETA 3-ANTAGONISTS
| Autor: | Giuseppe Saccomanni, Tiziana Cavallini, Rosamiria Greco, Clementina Manera, Pier Luigi Ferrarini, Vincenzo Calderone, Barbara Adinolfi, Muwaffag Badawneh, Lara Testai |
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| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Male
Beta-3 adrenergic receptor Magnetic Resonance Spectroscopy Spectrophotometry Infrared Adrenergic receptor Pyridines Stereochemistry Adrenergic beta-Antagonists Guinea Pigs Clinical Biochemistry Pharmaceutical Science In Vitro Techniques Biochemistry Chemical synthesis Structure-Activity Relationship Drug Discovery Animals Heart Atria Naphthyridines Rats Wistar Receptor Beta (finance) Molecular Biology Bicyclic molecule Chemistry Organic Chemistry Antagonist In vitro Rats Trachea Molecular Medicine Ethers |
| Popis: | Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence. More recently, some interesting theories about a negative role played by the cardio-depressant activity of myocardial beta(3)-adrenoceptors in heart failure, seemed to justify a clinical use of beta(3)-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the beta-antagonist properties of newly-synthesised (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and of 2,3-dihydrothiopyrano[2,3-b]pyridine were evaluated, in order to identify some useful structure-activity relationships, which might account for selectivity towards the three beta-subtypes and, in particular, the beta(3)-adrenoceptor. Among the various observations regarding possible structure-activity relationships, able to explain the pharmacodynamic patterns of the synthesised compounds on the three subtypes of beta-adrenoceptors, the most significant data derived from the evaluation of the beta(3)-blocking properties of some oximeethers of 1,8-naphthyridine derivatives. In these molecules, although the presence of the large substituents in position 7, such as 4-chloro-phenoxy- or 4-t-butyl-phenoxy groups determined a dramatic decline in both the beta(1)- and beta(2)-activities, this structural characteristic had a modest influence on the beta(3)-affinity, which was only slightly lower. Hence, this last structural requirement of oximeethers of 1,8-naphthyridine derivatives seems to represent a useful expedient to induce an appreciable selectivity towards the beta(3)-receptor, through a markedly negative effect on the beta(1)- and beta(2)-activities rather than an increase in the beta(3)-affinity. |
| Databáze: | OpenAIRE |
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