Study on Affinity Profile toward Native Human and Bovine Adenosine Receptors of a Series of 1,8-Naphthyridine Derivatives

Abstract

A new series of 1,8-naphthyridine derivatives (29-44 and 46-52) bearing various substituents in different positions on the heterocyclic nucleus were synthesized in order to analyze the effects produced on the affinity toward the bovine adenosine receptors. These derivatives represent an extension of our previous work on this class of compounds with high affinity toward A(1) adenosine receptors.(19) The results of radioligand binding assays indicate that a large number of the 1,8-naphthyridine derivatives proved to be A(1) selective, with a high affinity toward bovine adenosine receptors in the low nanomolar range, and one (29) in the subnanomolar range. Furthermore, the new series of 1,8-naphthyridine derivatives (29-44 and 46-52), together with the analogous derivatives 1-28 previously studied,(19) were tested to evaluate their affinity toward human cortical A(1) receptors and human striatal A(2A) receptors. The results indicate that all the 1,8-naphthyridine compounds generally possess a higher affinity toward the bovine A(1) receptor compared with the human A(1) receptor. As regards the affinity toward the A(2A) bovine receptor, only a few compounds possess a moderate affinity, which for some compounds remained approximately the same toward the A(2A) human receptor. A molecular modeling study of the docking of the 1,8-naphthyridine compounds with both the bovine and the human A(1) adenosine receptors was carried out with the aim of explaining the marked decrease in the affinity toward human A(1) adenosine receptors in comparison with bovine A(1) adenosine receptors. This study indicated that the structural differences, albeit small, of the active sites of the two receptors make differences in the dimensions of the site and this influenced the ability of the title compounds to interact with the two A(1) receptors.

Molecular modeling of A1 and A2A adenosine receptors: Comparison of rhodopsin‐ and β2‐adrenergic‐based homology models through the docking studies

“…Nevertheless, the lipophilic interactions of DPCPX presented here for the Rho-based A 1 AR are in consistence with most of the A 1 AR modeled previously. [104][105][106] Comparing the A 2A AR, it is worth to say that the model of b 2 -adrenergic-based A 2A AR showed the same binding ability for antagonists as the model described in ref. 61 as being the only one satisfying all the validation terms including the design and synthesis of new ligands which were active as it had been suggested by the model.…”

Molecular modeling of adenosine receptors: new results and trends

“…In Table IX are shown the main published A 1 receptor models and a brief description of the procedure used for their construction. 77,84,[98][99][100][101][102][103][104][105][106][107][108][109][110] With regards to the interaction of agonists, with the exception of the model proposed by Gutierrez et al (M7), the binding site is situated between TM3, TM6 and TM7. Furthermore, excluding the M6 model that analyzes bulky partial agonists, the ribose ring of the ligands interacts with T7.42(277) (serine in the bovine receptor) and H7.…”

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.…”

“…9). Although the amino acid sequence homology for the A 1 adenosine receptors is more than 90% between a number of different mammalian species, a subsequent paper by Ferrarini et al highlights the great differences in affinity achieved by compounds at the human and bovine receptors [120]. 7-Chloro-4-hydroxy-2-phenyl-1,8-naphthyridine (73) has a K i value of 300 nm at the human adenosine A 1 receptor, and also reports a drop in selectivity over the A 2A receptor.…”