The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3- d ]pyrimidine core in affecting adenosine A₁ and A_2A receptor affinity and selectivity profiles

摘要

Lucia Squarcialupi a , Marco Betti a , Daniela Catarzi a , Flavia Varano a , Matteo Falsini a , Annalisa Ravani b , Silvia Pasquini b , Fabrizio Vincenzi b , Veronica Salmaso c , Mattia Sturlese c , Katia Varani b , Stefano Moro c* & Vittoria Colotta a* a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy ; b Dipartimento di Scienze Mediche, Sezione di Farmacologia , Università di Ferrara , Ferrara , Italy ; c Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco , Università di Padova , Padova , Italy CONTACT Vittoria Colotta vittoria. colotta@unifi. it Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy ; Stefano Moro stefano. moro@unipd. it Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova , via Marzolo 5 , 35131 Padova , Italy Supplemental data for this article can be accessed here New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A₁ and/or A_2A receptor subtypes. On the whole, the novel derivatives 1 – 24 shared scarce or no affinities for the off-target hA_2B and hA₃ ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (K_i =?150?nM) and the best selectivity for the hA_2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA_2A (K_i =?123?nM) and A₁ AR affinity (K_i =?25?nM). The 5-phenethylamino moiety (compound 6 ) achieved nanomolar affinity (K_i =?11?nM) and good selectivity for the hA₁ AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15 – 24 bind the hA₁ AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.