Isoquinoline and quinazoline urea analogues as antagonists for the Human Adenosine A3 receptor
| Autor: | H. Van Der Goot, Wiro M. P. B. Menge, J.E. van Muijlwijk-Koezen, M.J. de Groot, F Frijtag von Drabbe Kunzel, Adriaan P. IJzerman, Henk Timmerman |
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| Přispěvatelé: | Medicinal chemistry, Software and Sustainability (S2) |
| Jazyk: | angličtina |
| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Stereochemistry Substituent CHO Cells Ring (chemistry) chemistry.chemical_compound Structure-Activity Relationship Cricetinae Drug Discovery medicine Quinazoline Animals Humans Isoquinoline Cells Cultured Cerebral Cortex Binding Sites Bicyclic molecule Receptor Adenosine A3 Receptors Purinergic P1 Adenosine A3 receptor Isoquinolines Adenosine receptor Adenosine Rats chemistry Purinergic P1 Receptor Antagonists Quinazolines Molecular Medicine medicine.drug |
| Zdroj: | van Muijlwijk-Koezen, J E, Timmerman, H, van der Goot, H, Menge, W M P B, Frijtag von Drabbe Kunzel, F, de Groot, M & IJzerman, A P 2000, ' Isoquinoline and quinazoline urea analogues as antagonists for the Human Adenosine A3 receptor ', Journal of the American Chemical Society . https://doi.org/10.1021/jm000002u Journal of the American Chemical Society. American Chemical Society |
| ISSN: | 0002-7863 |
| DOI: | 10.1021/jm000002u |
| Popis: | Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A(3) receptors. Series of N-phenyl-N'-quinazolin-4-ylurea derivatives and N-phenyl-N'-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure-affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A(3) receptor affinity in comparison to unsubstituted or aliphatic derivatives. Furthermore, the structure-affinity relationship of substituted phenylurea analogues was investigated. Substituents such as electron-withdrawing or electron-donating groups were introduced at different positions of the benzene ring to probe electronic and positional effects of substitution. Substitution on the 3- or 4-position of the phenyl ring decreased the adenosine A(3) receptor affinity. Substitution at position 2 with an electron-donating substituent, such as methyl or methoxy, increased human adenosine A(3) receptor affinity, whereas substitution on the 2-position with an electron-withdrawing substituent did not influence affinity. Combination of the optimal substituents in the two series had an additive effect, which led to the potent human adenosine A(3) receptor antagonist N-(2-methoxyphenyl)-N'-(2-(3-pyridyl)quinazolin-4-yl)urea (VUF5574, 10a) showing a K(i) value of 4 nM and being at least 2500-fold selective vs A(1) and A(2A) receptors. Compound 10a competitively antagonized the effect of an agonist in a functional A(3) receptor assay, i.e., inhibition of cAMP production in cells expressing the human adenosine A(3) receptor; a pA(2) value of 8.1 was derived from a Schild plot. In conclusion, compound 10a is a potent and selective human adenosine A(3) receptor antagonist and might be a useful tool in further characterization of the human A(3) receptor. |
| Databáze: | OpenAIRE |
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