title: Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists.
abstract: Scaffold selection involving an indole-to-indene core change led to the discovery of a series of indenylsulfonamides that act as 5-HT6 serotonin receptor agonists. The variety of the targeted ligands and their synthetic complexity required multistep synthetic approaches. The novel indenylsulfonamides exhibited variable binding affinities for the 5-HT6 receptor, and the in vitro primary binding profiles of the preferred compounds revealed them to be 5-HT6 receptor agonists with Ki values > or =4.5 nM. The structural changes responsible for enhancing the affinities indicated a directing effect modulated by the nature of the indene core, the substitution at the aminoethyl side chain, and especially by the aryl(heteroaryl)sulfonyl group on the indene 5-position. A representative of the family, the N-(inden-5-yl)imidazothiazole-5-sulfonamide (43), exhibited a high affinity and functioned as a potent full agonist for the 5-HT6 receptor (Ki = 4.5 nM, EC50 = 0.9 nM, Emax = 98%).
authors.affiliation: Laboratori de Química Orgànica, Departament de Farmacologia i Química Teraputica, Universitat de Barcelona, Avda. Joan XXIII s/n, E-08028 Barcelona, Spain. ealcalde@ub.edu
authors.forename: Ermitas
authors.initials: E
authors.lastname: Alcalde
authors.forename: Neus
authors.initials: N
authors.lastname: Mesquida
authors.forename: Sara
authors.initials: S
authors.lastname: López-Pérez
authors.forename: Jordi
authors.initials: J
authors.lastname: Frigola
authors.forename: Ramon
authors.initials: R
authors.lastname: Mercè
mesh_terms: D000818:Animals; D006801:Humans; D007192:Indenes / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D007668:Kidney / Q000166:cytology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: D007192:Indenes; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C093581:indene