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

1
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy
2
Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy
3
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(4), 159; https://doi.org/10.3390/ph12040159
Received: 26 September 2019 / Revised: 17 October 2019 / Accepted: 18 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases )
The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure–activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1H-imidazol-2-yl group at R2 position as an important feature for producing potent AR agonists. Moreover, the nature of the R1 substituent highly affects not only affinity/activity at the hA1 and hA2B ARs but also selectivity versus the other subtypes. Potent hA1 and hA2B AR ligands were developed, and among them, the 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile (3) is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA2A and hA3 ARs. This combined hA1/hA2B partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications. View Full-Text
Keywords: G protein-coupled receptors; adenosine A2B receptor ligands; adenosine A1 receptor ligands; aminopyridine-3,5-dicarbonitriles; ligand-adenosine receptor modeling studies G protein-coupled receptors; adenosine A2B receptor ligands; adenosine A1 receptor ligands; aminopyridine-3,5-dicarbonitriles; ligand-adenosine receptor modeling studies
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Catarzi, D.; Varano, F.; Varani, K.; Vincenzi, F.; Pasquini, S.; Dal Ben, D.; Volpini, R.; Colotta, V. Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists. Pharmaceuticals 2019, 12, 159.

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