title: Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands.
abstract: Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.
authors.affiliation: Department of Medicinal Chemistry, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain. jholenz@esteve.es
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Ramon
authors.initials: R
authors.lastname: Mercè
authors.forename: José Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: Xavier
authors.initials: X
authors.lastname: Guitart
authors.forename: Xavier
authors.initials: X
authors.lastname: Codony
authors.forename: Alberto
authors.initials: A
authors.lastname: Dordal
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Romero
authors.forename: Antoni
authors.initials: A
authors.lastname: Torrens
authors.forename: Josep
authors.initials: J
authors.lastname: Mas
authors.forename: Blas
authors.initials: B
authors.lastname: Andaluz
authors.forename: Susana
authors.initials: S
authors.lastname: Hernández
authors.forename: Xavier
authors.initials: X
authors.lastname: Monroy
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sánchez
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández
authors.forename: Raquel
authors.initials: R
authors.lastname: Pérez
authors.forename: Roger
authors.initials: R
authors.lastname: Cubí
authors.forename: Olga
authors.initials: O
authors.lastname: Sanfeliu
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
mesh_terms: D000262:Adenylyl Cyclases / Q000096:biosynthesis; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D048588:Benzoxazines; D007211:Indoles; D008024:Ligands; C500060:N-(3-(2-diethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide; C500058:N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide; C500059:N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloronaphthalene-2-sulfonamide; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; D000262:Adenylyl Cyclases