title: Positive allosteric modulators of the human sweet taste receptor enhance sweet taste.
abstract: To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cell-based assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 microM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3- to 2.5-fold at 50 microM. Further assay-guided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 microM) and SE-3 (200 microM) increased sucralose and sucrose potencies in the assay by 24- and 4.7-fold, respectively. In human taste tests, 100 microM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 microM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste.
authors.affiliation: Senomyx, Inc, La Jolla, CA 92121, USA. guy.servant@senomyx.com
authors.forename: Guy
authors.initials: G
authors.lastname: Servant
authors.forename: Catherine
authors.initials: C
authors.lastname: Tachdjian
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Tang
authors.forename: Sara
authors.initials: S
authors.lastname: Werner
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Poonit
authors.initials: P
authors.lastname: Kamdar
authors.forename: Goran
authors.initials: G
authors.lastname: Petrovic
authors.forename: Tanya
authors.initials: T
authors.lastname: Ditschun
authors.forename: Antoniette
authors.initials: A
authors.lastname: Java
authors.forename: Paul
authors.initials: P
authors.lastname: Brust
authors.forename: Nicole
authors.initials: N
authors.lastname: Brune
authors.forename: Grant E
authors.initials: GE
authors.lastname: DuBois
authors.forename: Mark
authors.initials: M
authors.lastname: Zoller
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
mesh_terms: D000494:Allosteric Regulation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013395:Sucrose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013549:Sweetening Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013649:Taste / Q000187:drug effects*; D013650:Taste Buds / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D013549:Sweetening Agents; D013876:Thiophenes; C431926:taste receptors, type 1; D013395:Sucrose; C026285:trichlorosucrose