Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists

Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8–13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the β-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).

The discovery of N1-arylsulfonyl-3-piperidin-3-yl-, -3-(1-methylpyrrolidin-2-ylmethyl)-, and -3-pyrrolidin-3-yl-1H-indoles as high affinity 5-HT6 receptor ligands is described. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a 24 nM full agonist, while N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives 11r and 11t behave as very potent antagonists.Figure optionsDownload as PowerPoint slide