N-arylsulfonylindole derivatives as serotonin 5-HT6 receptor ligands

A series of N-1-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT6 receptor with the 5-methoxy-1-benzenesulfonyl ana logue (19) having the highest affinity. Additionally, it was discovered tha t a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yI in the 2-positio n of the indole ring (43) can replace the arylsulfonyl substituent in the 1 -position with no loss of affinity. This suggested that the binding conform ation of the aminoethyl side chain at this receptor was toward the 4-positi on of the indole ring and was supported by the fact that the 4-(aminoethyl) indoles (45) also displayed high affinity, as did the conformationally rigi d 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19 , 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a fu nctional adenylate cyclase stimulation assay, 19 and 49 had no agonist acti vity, whereas 45 behaved as a partial agonist. Finally, it was shown that 1 9 had good activity in the 5-HT2A centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.