A Novel Class of Highly Potent and Selective A₁ Adenosine Antagonists:  Structure−Affinity Profile of a Series of 1,8-Naphthyridine Derivatives

Abstract

A series of 1,8-naphthyridine derivatives (12-36), bearing a phenyl group in position 2 and various substituents in positions 4 and 7, were synthesized in an attempt to obtain potent, selective antagonists for the A1 adenosine receptor subtype. The compounds were tested to evaluate their affinity for A1 compared with A2A and A3 adenosine receptor subtypes. In binding studies in bovine brain cortical membranes, most of the compounds showed an affinity for A1 receptors in the low nanomolar range and two in the subnanomolar range with an interesting degree of A1 versus A2A and A3 selectivity. Comparison of the 4-substituted derivatives indicated that 4-OH substitution, with a 4-quinoid structure, causes an increase in the A1 and A2A affinity and generally also in A1 selectivity. The kind of substitution in position 7 can greatly modulate the affinity: the most interesting substituents in this position seemed to be electron-withdrawing groups; in particular the 7-chloronaphthyridine 25d showed a remarkable selectivity (A2A/A1 ratio of 670, A3/A1 ratio of 14,000) associated with a higher A1 affinity (Ki = 0.15 nM). NMR studies on these compounds 12-36 indicated that the 4-OH-substituted ones prefer the tautomer in which the oxygen in position 4 is in the quinoid form and the nitrogen in position 1 is protonated. Theoretical calculations are in agreement with the NMR data.

Cytoskeletal protein 4.1G binds to the third intracellular loop of the A1 adenosine receptor and inhibits receptor action

“…After observing that 4.1G can influence A 1 AR ligand-binding properties, we next examined if 4.1G expression affects A 1 AR function. Because A 1 AR activation inhibits adenylate cyclase activity [22], we tested if 4.1G affected A 1 AR-mediated inhibition of cAMP accumulation in A 1 R-CHO cells.…”

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…In addition, although the cloning of the human adenosine A 1 receptor was reported in 1992, many even very recently developed compounds have not been tested at this receptor. One particularly relevant and very recent example are the naphthyridines reported by Ferrarini et al [119] [120]. The quoted 94% amino-acid homology between the human and bovine A 1 receptors concealed the discrepancies in affinity that was experienced by these compounds.…”

“…Siddiqi et al screened many compounds and found some affinity for naphthyridine derivatives [61]. More recently, Ferrarini et al published more lucrative substitution about the 1,8-naphthyridine ring [119]. At C(7), a number of halides were used, showing an almost equal effect across the board.…”

Expeditious Sonochemical Synthesis of New 1,8-Naphthyridine Derivatives and their Inhibitory Activity on HepG2 Cell Line

“…The assumed synthetic approach to obtain the target compounds was achieved by using the key intermediate 7-methyl-2-phenyl-1,8-naphthyridin-4(1H)-one (1) [27]. A series of 3-((substituted amino) methyl)-7-methyl -2-phenyl-1,8naphthyridin-4-one (2a-e) was obtained by the reaction of 7-methyl-2-phenyl-1,8-naphthyridinone (1) with paraformaldehyde and the appropriate secondary amine namely, piperidine, piperazine, morpholine, diethylamine and sulphanilimide in absolute ethanol, under either traditional heating or ultrasound irradiation through Mannich reaction to give the products 2a-e (Scheme 1).…”