N-Substituted Quinazolin- 2,4-diones as Adenosine Receptor Ligands

Six new N-substituted quinazolinones were synthesized and evaluated for their adenosine antagonistic activity using allergic mice model where 1, 3-dibenzyl and 1, 3-dibutyl-quinazolindiones were found to be potent than 1, 3-dimethylanalogues. They were not significant in controlling the neutrophil and lymphocyte count but effective in controlling the eosinophil influx. In adenosine receptor binding studies, 1,3-dimethyl and 1,3-dibutyl derivatives were found to have significant adenosine A1 receptor binding efficiency with Ki values 9nM and 10nM, respectively, while 1,3- dibenzyl-quinazolinone was found to have significant binding to adenosine A2A receptor showing the influence of alkyl and aralkyl groups present in these compounds. Thus, the present work indicates the possibility to explore quinazolindiones as adenosine receptor ligands.

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A model for the hydrogen-bonding interactions between adenosine receptor ligands and histidyl residues in the adenosine A1 receptor binding site, based on AMI calculations

Journal of Molecular Structure THEOCHEM ◽

10.1016/0166-1280(91)85215-s ◽

1991 ◽

Vol 231 ◽

pp. 175-184 ◽

Cited By ~ 7

Author(s):

Eleonora M. Van Der Wenden ◽

Philip J.M. Van Galen ◽

Adriaan P. Ijzerman ◽

Willem Soudijn

Keyword(s):

Hydrogen Bonding ◽

Binding Site ◽

Receptor Binding ◽

Adenosine Receptor ◽

Receptor Ligands ◽

Receptor Binding Site ◽

Hydrogen Bonding Interactions ◽

Adenosine A1 ◽

A1 Receptor ◽

Adenosine Receptor Ligands

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Identification of the A2 adenosine receptor binding subunit by photoaffinity crosslinking

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.86.17.6572 ◽

1989 ◽

Vol 86 (17) ◽

pp. 6572-6576 ◽

Cited By ~ 50

Author(s):

W W Barrington ◽

K A Jacobson ◽

A J Hutchison ◽

M Williams ◽

G L Stiles

Keyword(s):

Receptor Binding ◽

Adenosine Receptor ◽

Crosslinking Agent ◽

Camp Production ◽

Binding Studies ◽

High Affinity ◽

Receptor Pharmacology ◽

A1 Receptor ◽

Photoaffinity Crosslinking ◽

Binding Subunit

A high-affinity iodinated agonist radioligand for the A2 adenosine receptor has been synthesized to facilitate studies of the A2 adenosine receptor binding subunit. The radioligand 125I-labeled PAPA-APEC (125I-labeled 2-[4-(2-[2-[(4- aminophenyl)methylcarbonylamino]ethylaminocarbonyl]- ethyl)phenyl]ethylamino-5'-N-ethylcarboxamidoadenosine) was synthesized and found to bind to the A2 adenosine receptor in bovine striatal membranes with high affinity (Kd = 1.5 nM) and A2 receptor selectivity. Competitive binding studies reveal the appropriate A2 receptor pharmacologic potency order with 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)-N6-[(R)-1-methyl- 2-phenylethyl]adenosine (R-PIA) greater than (+)-N6-[(S)-1-methyl-2- phenylethyl]adenosine (S-PIA). Adenylate cyclase assays, in human platelet membranes, demonstrate a dose-dependent stimulation of cAMP production. PAPA-APEC (1 microM) produces a 43% increase in cAMP production, which is essentially the same degree of increase produced by 5'-N- ethylcarboxamidoadenosine (the prototypic A2 receptor agonist). These findings combined with the observed guanine nucleotide-mediated decrease in binding suggest that PAPA-APEC is a full A2 agonist. The A2 receptor binding subunit was identified by photoaffinity-crosslinking studies using 125I-labeled PAPA-APEC and the heterobifunctional crosslinking agent N-succinimidyl 6-(4'-azido-2'-nitrophenylamino)hexanoate (SANPAH). After covalent incorporation, a single specifically radiolabeled protein with an apparent molecular mass of 45 kDa was observed on NaDodSO4/PAGE/autoradiography. Incorporation of 125I-labeled PAPA-APEC into this polypeptide is blocked by agonists and antagonists with the expected potency for A2 receptors (see above) and is decreased in the presence of 10(-4) M guanosine 5'-[beta, gamma-imido]triphosphate. Photoaffinity crosslinking of the A1 adenosine receptor binding subunit with 125I-labeled 8-[4-[2-(4- aminophenylacetylamino)ethyl]carbonylmethyloxyphenyl]-1,3-di propylxanthine (PAPAXAC) (an A1 selective photoaffinity probe) in the same tissue reveals a 38-kDa peptide that exhibits the appropriate A1 receptor pharmacology. 125I-labeled PAPA-APEC, therefore, has identified the A2 receptor binding subunit as a 45-kDa protein that is unique and distinct from the A1 binding subunit.

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