title: Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors.
abstract: 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 Ki 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Sikazwe
authors.forename: Mikhail L
authors.initials: ML
authors.lastname: Bondarev
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Jagadeesh B
authors.initials: JB
authors.lastname: Rangisetty
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D008024:Ligands; D010627:Phenethylamines; D010879:Piperazines; D011758:Pyrroles; D011985:Receptors, Serotonin; D013449:Sulfonamides; C097216:serotonin 6 receptor; C031503:phenylpiperazine