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

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 21; pp. 4780 - 4785
• Main Authors: COLE, Derek C, LENNOX, William J, STOCK, Joseph R, ELLINGBOE, John W, MAZANDARANI, Hossein, SMITH, Deborah L, GUOMING ZHANG, TAWA, Gregory J, SCHECHTER, Lee E
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.11.2005
• Subjects: Adenylyl Cyclases - metabolism; Biological and medical sciences; Cyclic AMP - biosynthesis; Humans; Medical sciences; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Binding; Receptors, Serotonin - drug effects; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Structure-Activity Relationship; Tryptamines - chemical synthesis; Tryptamines - chemistry; Tryptamines - pharmacology; Agonist; Nitrogen heterocycle; 5-HT6 serotonin receptor; Tryptamine derivatives; Selectivity; Pyrrolidine derivatives; Thiophene derivatives; 5-HT6; Structure activity relation; Piperidine derivatives; Production; Bicyclic compound; Aromatic compound; Antagonist; Chemical synthesis; Molecular rigidity; Sulfonamide; Serotonin; Benzene derivatives; Cyclic AMP; Steric hindrance; In vitro; N1-Arylsulfonyltryptamine; Carboline derivatives; Receptor; Affinity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.07.028

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 beta-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).