Binding of Sulfonyl-Containing Arylalkylamines at Human 5-HT6 Serotonin Receptors

• Published in: Journal of medicinal chemistry 2006-08, Vol.49 (17), p.5217-5225
• Main Authors: Sikazwe, Donald, Bondarev, Mikhail L, Dukat, Małgorzata, Rangisetty, Jagadeesh B, Roth, Bryan L, Glennon, Richard A
• Format: Article
• Language: English
• Subjects: Binding Sites; Binding, Competitive - drug effects; Biological and medical sciences; Humans; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phenethylamines - chemical synthesis; Phenethylamines - chemistry; Phenethylamines - pharmacology; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Serotonin - chemistry; Receptors, Serotonin - drug effects; Serotoninergic system; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060469q

Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT6 serotonin receptors, but it has been difficult relating the binding mode(s) of such agents to one another, even though many possess a common SO2 moiety, to identify a common pharmacophore model(s). On the basis of the hypothesis that an ergoline-type conformation might be important for the binding of some sulfonamide-containing arylalkylamines, we prepared for examination at h5-HT6 receptors a series of compounds, including phenylethylamines 6, pyrroloethylamine 7, and phenylpiperazines 9. The results (with K i values ranging from about 1 nM to >1000 nM) suggest that many of these agents likely bind in a related fashion, and structure−affinity studies indicate that the benzenesulfonamide portion of the phenylethylamine and phenylpiperazine analogues can be “reversed”, abbreviated to a sulfone, and moved to an adjacent position with relatively little impact on affinity. Although a benzenesulfonamide (or related arylsulfonamide) group might be common to various 5-HT6 ligands, there appears to be some latitude with regard to the specific constitution and location of the sulfonamide moiety even within the same arylalkylamine structural framework. A pharmacophore model is presented to account for some of the current findings.