title: 2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: the discovery of alpha1a subtype selective 2'-alkylsulfonyl-substituted analogues.
abstract: A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.
authors.affiliation: GlaxoSmithKline Research Laboratories, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hodson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bishop
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Frank
authors.initials: F
authors.lastname: Navas
authors.forename: Deanna T
authors.initials: DT
authors.lastname: Garrison
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bigham
authors.forename: David L
authors.initials: DL
authors.lastname: Saussy
authors.forename: James A
authors.initials: JA
authors.lastname: Liacos
authors.forename: Paul E
authors.initials: PE
authors.lastname: Irving
authors.forename: M Jeffrey
authors.initials: MJ
authors.lastname: Gobel
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Sherman
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C455802:2'-methylsulfonyl-5'-methoxy-2-(anilinomethyl)imidazoline; C547713:ADRA1A protein, human; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013450:Sulfones; D000242:Cyclic AMP; D002118:Calcium