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

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

  • J Med Chem. 2019 Aug 8;62(15):6894-6912. doi: 10.1021/acs.jmedchem.9b00106.
Marco Betti 1,  Daniela Catarzi 1,  Flavia Varano 1,  Matteo Falsini 1,  Katia Varani 2,  Fabrizio Vincenzi 2,  Silvia Pasquini 2,  Lorenzo di Cesare Mannelli 3,  Carla Ghelardini 3,  Elena Lucarini 3,  Diego Dal Ben 4,  Andrea Spinaci 4,  Gianluca Bartolucci 1,  Marta Menicatti 1,  Vittoria Colotta 1
Affiliations

Affiliations

  • 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 Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia , Università degli Studi di Firenze , Viale Pieraccini, 6 , 50139 Firenze , Italy.
  • 4 Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy.
PMID: 31306001 DOI: 10.1021/acs.jmedchem.9b00106
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 high to good human (h) A1AR affinity and an inverse agonist profile. While most of the compounds are hA1AR-selective, some derivatives behave as mixed hA1AR inverse agonists/A2A and A2B AR antagonists. The latter compounds (9-12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of 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 structure-activity relationships.

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