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 |
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Authors: | Altenbach Robert J Khilevich Albert Kolasa Teodozyj Rohde Jeffrey J Bhatia Pramila A Patel Meena V Searle Xenia B Yang Fan Bunnelle William H Tietje Karin Bayburt Erol K Carroll William A Meyer Michael D Henry Rodger Buckner Steven A Kuk Jane Daza Anthony V Milicic Ivan V Cain John C Kang Chae H Ireland Lynne M Carr Tracy L Miller Thomas R Hancock Arthur A Nakane Masaki Esbenshade Timothy A Brune Michael E O'Neill Alyssa B Gauvin Donna M Katwala Sweta P Holladay Mark W Brioni Jorge D Sullivan James P |
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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 |
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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. |
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