Synthesis and Biological Evaluation of 2,3,5-Substituted [1,2,4]Thiadiazoles as Allosteric Modulators of Adenosine Receptors

Abstract

A number of 2,3,5-substituted [1,2,4]thiadiazole analogues of SCH-202676 (N-(2,3-diphenyl[1,2,4]thiadiazole-5(2H)-ylidene)methanamine, 7a) were synthesized and tested as potential allosteric modulators of adenosine receptors. All compounds were capable of displacing the binding of the radiolabeled agonist [(3)H]CCPA to human A(1) adenosine receptors, whereas modest and varying effects were observed on the binding of [(3)H]DPCPX, a radiolabeled antagonist for this receptor subtype. Four compounds, 7a (SCH-202676), 7k (LUF5792), 7l (LUF5794), and 8e (LUF5789), were selected for more detailed characterization. They all proved allosteric inhibitors of agonist binding, with 7k being most potent, whereas their effects on antagonist binding were more ambiguous. Subsequently, experiments were done on human adenosine A(2A) and A(3) receptors. Compounds 7a and 7l displayed peculiar displacement characteristics of both radiolabeled agonist and antagonist binding to A(2A) receptors, whereas 7a showed some activity on A(3) receptors.

Allosteric Modulation of K v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

“…This suggests that these ligands bind to the K v 11.1 channel at sites distinct from that of dofetilide, indicative of an allosteric mode of action. 10,28,29 The binding of a drug to a receptor at an allosteric site (ie, a site topologically distinct from that of the test ligand) triggers a conformational change within the receptor, ultimately causing an alteration of the ligand's dissociation rate from its cognate (ie, orthosteric) binding site. 10,30 Altered ligand dissociation rates have been found representative of allosteric interactions in various drug targets, such as muscarinic and adenosine receptors.…”

Photosynthesis of novel 4-arylamino-2-phenyl-6-substituted-quinazoline

“…21 The photocyclization of thiourea derivative 1a with a high-pressure mercury lamp (365 nm) in acetonitrile under N2 protection at room temperature was chosen as a model reaction. Initially, the photochemical experiment in the presence of organic base (triethylamine) and inorganic base (sodium hydroxide) were explored.…”

Ferrocenylimidazoline palladacycles as efficient catalysts for the aza‐Claisen rearrangement reaction of allylic imidates

“…The N-p-tolyl-benzimidoyl chloride, [9] N-(p-methoxylphenyl)-benzimidoyl chloride, [9] N-(p-chlorophenyl)-benzimidoyl chloride, [10] N-(m-chlorophenyl)-benzimidoyl chloride, [9] N-(pnitrophenyl)-benzimidoyl chloride [11] and ferrocenylimidazoline palladacycles 1a-f [5] were prepared according to the reported procedures. Unless noted, all other chemicals were commercial products and used without further purification.…”