New 2-arylpyrazolo[3,4-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies.
This paper reports the study of some 2-arylpyrazolo[3,4-c]quinolin-4-ones, 4-amines, and 4-amino-substituted derivatives designed as human A3 adenosine receptor (AR) antagonists. Most of the herein reported compounds showed a nanomolar affinity toward the hA3 receptor subtype and different degrees of selectivity that resulted to be strictly dependent on the presence and nature of the substituent on the 4-amino group. Bulky and lipophilic acyl groups, as well as the benzylcarbamoyl residue, afforded highly potent and selective hA3 receptor antagonists. The selected 4-diphenylacetylamino-2-phenylpyrazoloquinoline (25) and 4-dibenzoylamino-2-(4-methoxyphenyl)pyrazoloquinoline (36), tested in an in vitro rat model of cerebral ischemia, prevented the irreversible failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. The observed structure-affinity relationships of this class of antagonists were also exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach.
Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Università di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. vittoria.colatta@unifi.it
Vittoria
V
Colotta
Daniela
D
Catarzi
Flavia
F
Varano
Francesca
F
Capelli
Ombretta
O
Lenzi
Guido
G
Filacchioni
Claudia
C
Martini
Letizia
L
Trincavelli
Osele
O
Ciampi
Anna Maria
AM
Pugliese
Felicita
F
Pedata
Andrea
A
Schiesaro
Erika
E
Morizzo
Stefano
S
Moro
D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004594:Electrophysiology; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission; D013737:Testis / Q000378:metabolism
C523817:4-dibenzoylamino-2-(4-methoxyphenyl)pyrazoloquinoline; C523816:4-diphenylacetylamino-2-phenylpyrazoloquinoline; D058918:Adenosine A3 Receptor Antagonists; D001549:Benzamides; D008024:Ligands; D011720:Pyrazoles; D011804:Quinolines; D000242:Cyclic AMP