Indene-based frameworks targeting the 5-HT6 serotonin receptor: Ring constraint in indenylsulfonamides using cyclic amines and structurally abbreviated counterparts

Abstract Further studies in quest of 5-HT 6 serotonin receptor ligands led to the design and synthesis of a few selected examples of N -(inden-5-yl)sulfonamides with a ring-constrained aminoethyl side chain at the indene 3-position, some of which exhibited a high binding affinity, such as the pyrrolidine analogue 28 ( K i  = 3 nM). Moreover, the structurally abbreviated N -(inden-5-yl)sulfonamides showed K i values ⩾43 nM, which indicates that neither the N , N -aminoethyl nor the conformationally restricted aminoethyl side arm at the indene 3-position are required for binding. Selected compounds were then tested in a functional cAMP stimulation assay and found to act as 5-HT 6 antagonists, although with moderate potency at the micromolar level.