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.
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| Abstract |
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.
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| Authors | Vittoria Colotta, Daniela Catarzi, Flavia Varano, Francesca Capelli, Ombretta Lenzi, Guido Filacchioni, Claudia Martini, Letizia Trincavelli, Osele Ciampi, Anna Maria Pugliese, Felicita Pedata, Andrea Schiesaro, Erika Morizzo, Stefano Moro |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 17 Pg. 4061-74 (Aug 23 2007) ISSN: 0022-2623 [Print] United States |
| PMID | 17665891 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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