Synthesis and β-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of β3-antagonists Original Research Article

Drugs acting on β1- and β2-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 β receptors, the β3-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of β3-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 β3-adrenoceptors in heart failure, seemed to justify a clinical use of β3-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the β-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 β-subtypes and, in particular, the β3-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 β-adrenoceptors, the most significant data derived from the evaluation of the β3-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 β1- and β2-activities, this structural characteristic had a modest influence on the β3-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 β3-receptor, through a markedly negative effect on the β1- and β2-activities rather than an increase in the β3-affinity.