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.
Colotta
Vittoria
V
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
Catarzi
Daniela
D
Varano
Flavia
F
Capelli
Francesca
F
Lenzi
Ombretta
O
Filacchioni
Guido
G
Martini
Claudia
C
Trincavelli
Letizia
L
Ciampi
Osele
O
Pugliese
Anna Maria
AM
Pedata
Felicita
F
Schiesaro
Andrea
A
Morizzo
Erika
E
Moro
Stefano
S
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