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Synthesis and Biological Evaluation of a New Series of 2,3,5-Substituted [1,2,4]-Thiadiazoles as Modulators of Adenosine A1 Receptors and Their Molecular Mechanism of Action

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journal contribution
posted on 24.02.2005, 00:00 by Anikó Göblyös, Henk de Vries, Johannes Brussee, Adriaan P. IJzerman
We synthesized two series (7ai and 8ai) of 2,3,5-substituted [1,2,4]-thiadiazole analogues of SCH-202676 (7a, 2,3-diphenyl-5-N-methylimino-2H-[1,2,4]-thiadiazole) with emphasis on the N-imino substituent. Compounds 7ag,i and 8ag at a final concentration of 1 μM significantly inhibited [3H]CCPA (2-chloro-N6- cyclopentyladenosine) agonist binding to human A1 adenosine receptors. At the same concentration, all compounds appeared to increase [3H]DPCPX (1,3-dipropyl-8-cyclopentylxanthine) antagonist binding. Compound 7a and LUF5855 (7g) were selected for further characterization and studied in both equilibrium and kinetic radioligand binding experiments. The results suggest a nonstoichiometric interaction with the receptor. Further bioanalytical procedures (HPLC and MS) provided proof for an unusual receptor interaction in which 7a and 7g upon incubation were transformed into their corresponding thioureas 5a and 5g. We suggest that the thiadiazoles are sulfhydryl modifying agents rather than allosteric modulators, as they appear to reversibly modify the sulfhydryl groups of cysteine residues in cell membrane preparations.