title: Optimization of isochromanone based urotensin II receptor agonists.
abstract: A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified, with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one being the most potent compound showing an EC₅₀-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.
authors.affiliation: Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lehmann
authors.forename: Erika A
authors.initials: EA
authors.lastname: Currier
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C559342:3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one; D001549:Benzamides; D002839:Chromans; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human