Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

Abstract

A new series of amino-3,5-dicyanopyridines (1-31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having from high to good human (h) A 1 AR affinity and an inverse agonist profile. While most of the compounds are hA 1 AR selective, some derivatives behave as mixed hA 1 AR inverse agonists/A 2A and A 2B AR antagonists. These latter (compound 9-12) showed to reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similarly to the non-selective AR antagonist caffeine, taken as reference compound. Along with the pharmacological evaluation, chemical stability of the methyl 3- (((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available SARs.

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

“…Interestingly, all these compounds showed antagonist activity at the A 1 AR, with affinity data in the low nanomolar range in several cases (as examples are reported compounds 20-24; Figure 1; Table 1). The replacement of the 4-phenyl ring with a 2-furyl group seems critical for the agonist-to-antagonist shift in the intrinsic activity of the compounds [62].…”

“…Analogously, the modification of the A 1 AR agonist Capadenoson (1) through the replacement of the exocyclic amine with a pyrrolidinyl group led to the development of Neladenoson (2), another A 1 AR agonist with improved selectivity versus the A 2B AR (see EC 50 data of 1 and 2, Table 1). However, this rule appears to not always be respected in the case of non-nucleoside derivatives, since some above-described antagonists presenting analogue docking conformations were modified with the insertion of alkyl groups in the exocyclic amine but the obtained affinities at ARs were generally lower respect to the unmodified compounds [62].…”

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

“…The growing interest in this class is also dictated by the fact that non-nucleoside AR agonists seem to be more versatile for pharmacological studies, showing fewer species differences than the adenosine-like ones [4]. Moreover, the studies carried out to date are sufficient to underline the versatility of the amino-3,5-dicyanopyridine scaffold for producing AR ligands with not only a wide range of affinities but, interestingly, with different degrees of efficacy at the different ARs [11,12,[14][15][16][17][18][19].…”

“…Elimination of the 6-substituent was realized in compound 18 which was synthesized by catalytic reduction (10% Pd/C) of 42 with hydrogen at 30 Psi in absolute EtOH. Finally, the 6-[(2-hydroxyethyl)amino]-derivative 19 was synthesized (Scheme 3) starting from the intermediate 27 [24] by exploiting the good property of the 6-phenylthio function as the leaving group in nucleophilic substitution [15]. The reaction was performed at 100 °C in DMF using an excess of 2-aminoethanol as nucleophile.…”

“…The obtained hA2BAR homology model was checked using the Protein Geometry Monitor application within MOE (Molecular Operating Environment 2019.0101) [30] by inspecting the structural quality of the protein model (backbone bond lengths, angles, and dihedrals, Ramachandran φ-ψ dihedral plots, and quality of side chain rotamer and non-bonded contact). The two AR structures were then [24] by exploiting the good property of the 6-phenylthio function as the leaving group in nucleophilic substitution [15]. The reaction was performed at 100 °C in DMF using an excess of 2-aminoethanol as nucleophile.…”