Influence of the 5-HT6 Receptor on Acetylcholine Release in the Cortex:  Pharmacological Characterization of 4-(2-Bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a Potent and Selective 5-HT6 Receptor Antagonist

• Published in: Journal of medicinal chemistry 2003-03, Vol.46 (7), p.1273-1276
• Main Authors: Riemer, Claus, Borroni, Edilio, Levet-Trafit, Bernard, Martin, James R, Poli, Sonia, Porter, Richard H. P, Bös, Michael
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Administration, Oral; Animals; Avoidance Learning - drug effects; Biological and medical sciences; Biological Availability; Blood-Brain Barrier; Cell Line; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Half-Life; Humans; In Vitro Techniques; Injections, Intravenous; Medical sciences; Microdialysis; Microsomes, Liver - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Serotoninergic system; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm021085c

A small series of aryl pyridyl sulfones has been prepared and investigated for its 5-HT6 receptor binding properties. Thereof, pyrrolidinyl derivative 11 proved to be a very potent (pK i 9) and selective 5-HT6 receptor antagonist. By means of in vivo microdialysis in the frontal cortex and a passive avoidance paradigm, where 11 reversed a scopolamine induced retention deficit, a functional correlation between 5-HT6 receptors and cholinergic neurotransmission could be shown, supporting the therapeutic potential of 5-HT6 receptors in the treatment of cognitive deficits.