Selective A3 Adenosine Receptor Antagonists: Water-Soluble 3,5-Diacyl-1,2,4-trialkylpyridinium Salts and Their Oxidative Generation from Dihydropyridine Precursors
| Autor: | Rongyuan Xie, Neli Melman, Kenneth A. Jacobson, An-Hu Li, Xiao-duo Ji, Mark E. Olah, Gary L. Stiles |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Dihydropyridines
Pyridinium Compounds CHO Cells Oxidative phosphorylation In Vitro Techniques Ligands Thioester Chemical synthesis Radioligand Assay Structure-Activity Relationship Cricetinae Drug Discovery medicine Animals Humans Enzyme Inhibitors Cerebral Cortex chemistry.chemical_classification biology Receptor Adenosine A3 Dihydropyridine In vitro Rats Enzyme Purinergic P1 Receptor Antagonists Solubility chemistry Biochemistry Enzyme inhibitor Adenylyl Cyclase Inhibitors biology.protein Molecular Medicine Oxidation-Reduction Adenosine A2B receptor medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:4232-4238 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990234x |
| Popis: | A(3) adenosine receptor antagonists are sought for their potential antiinflammatory, antiasthmatic, and antiischemic properties. We have found that 3,5-diacyl-1,2,4-trialkyl-6-phenylpyridinium derivatives constitute a novel class of selective A(3) adenosine receptor antagonists. The structure-activity relationships of this class of antagonists, incorporating the 3-thioester, have been explored. The most potent analogue in this group was 2, 4-diethyl-1-methyl-3-(ethylsulfanylcarbonyl)-5-ethyloxycarbonyl -6-phe nylpyridinium iodide (11), which had an equilibrium inhibition constant (K(i)) value of 219 nM at human A(3) receptors (binding of [(125)I]AB-MECA (N(6)-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyladenosine)) expressed in Chinese hamster ovary (CHO) cells and10 microM at rat brain A(1) and A(2A) receptors and at recombinant human A(2B) receptors. Compound 11 could be generated through oxidation of the corresponding 3,5-diacyl-1,2,4-trialkyl-6-phenyl-1,4-dihydropyridine, 24, with iodine or in the presence of rat brain homogenates. A 6-cyclopentyl analogue was shown to increase affinity at human A(3) receptors upon oxidation from the 1-methyl-1,4-dihydropyridine analogue, 25, to the corresponding pyridinium derivative, 23 (K(i) 695 nM), suggesting a prodrug scheme. Homologation of the N-methylpyridinium derivatives to N-ethyl and N-propyl at the 1-position caused a progressive reduction in the affinity at A(3) receptors. Modifications of the alkyl groups at the 2-, 3-, 4-, and 5-positions failed to improve potency in binding at A(3) receptors. The pyridinium antagonists are not as potent as other recently reported, selective A(3) receptor antagonists; however, they display uniquely high water solubility (43 mM for 11). Compound 11 antagonized the inhibition of adenylate cyclase elicited by IB-MECA in CHO cells expressing the human A(3) adenosine receptor, with a K(B) value of 399 nM, and did not act as an agonist, demonstrating that the pyridinium salts are pure antagonists. |
| Databáze: | OpenAIRE |
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