ABSTRACT
A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-HT6 receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC50=29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT6 receptor radioligand binding assay (Ki=1.7 nM). A screening of 5-HT2A and 5-HT2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT6 receptor ligands.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Cell Line , Humans , Pyrimidines/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT(6) receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT(6)R antagonists. The most active 5-HT(6)R antagonists have IC(50) <100 nM in a functional assay, and K(i) <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.
