title: Alpha(1)-adrenoceptor activation: a comparison of 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles to related 2-imidazolines.
abstract: Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and alpha(1)-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate alpha(1)-adrenoceptors.
authors.affiliation: GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hodson
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bigham
authors.forename: Deanna T
authors.initials: DT
authors.lastname: Garrison
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gobel
authors.forename: Paul E
authors.initials: PE
authors.lastname: Irving
authors.forename: James A
authors.initials: JA
authors.lastname: Liacos
authors.forename: Frank
authors.initials: F
authors.lastname: Navas
authors.forename: David L
authors.initials: DL
authors.lastname: Saussy
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Sherman
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bishop
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000737:chemistry*; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000814:Aniline Compounds; D007093:Imidazoles; D010647:Phenyl Ethers; D011994:Recombinant Proteins