title: 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.
abstract: We synthesized two series (7a-i and 8a-i) 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 7a-g,i and 8a-g at a final concentration of 1 microM significantly inhibited [(3)H]CCPA (2-chloro-N(6)- cyclopentyladenosine) agonist binding to human A(1) adenosine receptors. At the same concentration, all compounds appeared to increase [(3)H]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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Anikó
authors.initials: A
authors.lastname: Göblyös
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007700:Kinetics; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D013830:Thiadiazoles