Heterocyclic analogs of benzanilide derivatives as potassium channel activators. IX

On the basis of our previous works, addressed to synthesise new activators of BK potassium channels, and of many suggestions from the international literature, a simple pharmacophoric model, consisting of two suitably substituted phenyl rings bound to various kinds of linkers, was hypothesised. In particular, the effectiveness of the amidic linker was demonstrated, since several benzanilide derivatives showed interesting BK-opener properties. As a development of these benzanilides, in this work we introduced heterocyclic substituents, replacing the aryl ring on the acid side or on the basic one of the amide linker of the above pharmacophore. The pharmacological results indicated some relevant remarks about the structural requirements, needed for a satisfactory BK-opener activity. In particular, the presence of a phenolic function, with a possible H-bond donor role, has been confirmed. Furthermore, the presence of nitrogen heterocycles on the acid side of the amide linker seems to be a negative requirement, while furan and thiophene were well tolerated. On the contrary, the introduction of insaturated heterocyclic rings (pyridine and thiazole) on the basic side of the amide linker, led to satisfactory biological activity, while the presence of aliphatic heterocycles lowered the pharmacological effect. (c) 2006 Elsevier SAS. All rights reserved

Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A(1) adenosine receptors

We describe here the synthesis and biological activity of new 8-azaadenines bearing both a phenyl group on C(2) and a 9-benzyl group substituted in the ortho position with a Cl or a F atom or a CF3 group, to verify the synergistic effect of a combination of these substitution patterns on binding with the A1 adenosine receptors. In position N6 aliphatic and cycloaliphatic substituents were chosen which had been shown to bind well with the A1 receptors. Because of the high lipophilicity of these kinds of molecules, we also introduced a hydroxyalkyl substituent in the same position. The compounds obtained generally showed a very good affinity and selectivity for A1 receptors. Some of the compounds showed Ki in the nanomolar range, one even in the subnanomolar range (0.6 nM). Molecular docking calculations were performed in order to evaluate the interaction energies between the bovine A1 receptor model and the selected ligands, and then to correlate these energies with biological activities of the ligands as obtained from the experiments. Molecular docking analysis suggests different binding modes towards A1 receptors that are plausible for these ligands