title: The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs.
abstract: Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT(6) receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the wide notspread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the "arylsulfonyl" nor the "tryptamine" portion of these compounds is essential for binding or for antagonist action, and some such derivatives even display agonist action. The present review describes many of the currently available 5-HT(6) receptor ligands and, unlike prior reviews, provides a narrative of the thinking (where possible) that led to their design, synthesis, and evaluation. The arylsulfonyltryptamines are also used as the structural basis of attempts to relate various structure-types to one another to afford a better understanding of the overall structural requirements for 5-HT(6) receptor binding.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Box 980540, Virginia Commonwealth University, Richmond, VA 23298-0540,USA. glennon@vcu.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.forename: Uma
authors.initials: U
authors.lastname: Siripurapu
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Renata
authors.initials: R
authors.lastname: Kolanos
authors.forename: Mikhail L
authors.initials: ML
authors.lastname: Bondarev
authors.forename: Donald
authors.initials: D
authors.lastname: Sikazwe
authors.forename: Mase
authors.initials: M
authors.lastname: Lee
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
mesh_terms: D002626:Chemistry, Pharmaceutical; D008024:Ligands; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014363:Tryptamines; C097216:serotonin 6 receptor