title: Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist.
abstract: Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA. Robert.j.altenbach@abbott.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Albert
authors.initials: A
authors.lastname: Khilevich
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rohde
authors.forename: Pramila A
authors.initials: PA
authors.lastname: Bhatia
authors.forename: Meena V
authors.initials: MV
authors.lastname: Patel
authors.forename: Xenia B
authors.initials: XB
authors.lastname: Searle
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Karin
authors.initials: K
authors.lastname: Tietje
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: Rodger
authors.initials: R
authors.lastname: Henry
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Jane
authors.initials: J
authors.lastname: Kuk
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Daza
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Milicic
authors.forename: John C
authors.initials: JC
authors.lastname: Cain
authors.forename: Chae H
authors.initials: CH
authors.lastname: Kang
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ireland
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Carr
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Alyssa B
authors.initials: AB
authors.lastname: O'Neill
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: Sweta P
authors.initials: SP
authors.lastname: Katwala
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; C547721:Adra1d protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D007093:Imidazoles; C445279:N-(5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl)methanesulfonamide; D009281:Naphthalenes; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes