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.

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.

Citation

Robert J Altenbach, Albert Khilevich, Teodozyj Kolasa, Jeffrey J Rohde, Pramila A Bhatia, Meena V Patel, Xenia B Searle, Fan Yang, William H Bunnelle, Karin Tietje, Erol K Bayburt, William A Carroll, Michael D Meyer, Rodger Henry, Steven A Buckner, Jane Kuk, Anthony V Daza, Ivan V Milicic, John C Cain, Chae H Kang, Lynne M Ireland, Tracy L Carr, Thomas R Miller, Arthur A Hancock, Masaki Nakane, Timothy A Esbenshade, Michael E Brune, Alyssa B O'Neill, Donna M Gauvin, Sweta P Katwala, Mark W Holladay, Jorge D Brioni, James P Sullivan. 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. Journal of medicinal chemistry. 2004 Jun 3;47(12):3220-35

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PMID: 15163201

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