1,2,3,4-Tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands

An investigation of the structure–affinity relationships for the binding of 4-(N,N-dimethylaminomethyl)-N9-arylsulfonyl-9H-1,2,3,4-tetrahydrocarbazoles (conformationally-constrained analogues of the benzenesulfonyltryptamine 5-HT6 antagonist MS-245) at human 5-HT6 receptors revealed that various arylsulfonyl substituents are tolerated and that the 4-(N,N-dimethylaminomethyl) group is not required for binding. In particular, N9-(4-aminobenzenesulfonyl)-9H-1,2,3,4-tetrahydrocarbazole (20, Ki=29 nM) was found to bind with high affinity and represents the first member of a new structural class of agents with 5-HT6 antagonist properties (pA2=7.0; cAMP hydrolysis assay).