Synthesis and Structure−Activity Studies on N-[5-(1H-Imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an Imidazole-Containing α1A-Adrenoceptor Agonist
| Autor: | Rodger F. Henry, Steven A. Buckner, Michael E. Brune, Tracy L. Carr, Sweta P. Katwala, Masaki Nakane, Thomas R. Miller, Arthur A. Hancock, Jorge D. Brioni, Anthony V. Daza, Michael Meyer, John C Cain, William A. Carroll, Robert J. Altenbach, Albert Khilevich, Lynne M. Ireland, Fan Yang, Mark W. Holladay, Meena V. Patel, Rohde Jeffrey J, William H. Bunnelle, Chae H Kang, Timothy A. Esbenshade, Donna M. Gauvin, Teodozyj Kolasa, James P. Sullivan, Karin R. Tietje, Jane Kuk, Pramila Bhatia, Alyssa B. O'Neill, Searle Xenia B, Ivan Milicic, Erol K. Bayburt |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Agonist Tetrahydronaphthalenes Stereochemistry medicine.drug_class Alpha (ethology) Blood Pressure In Vitro Techniques Naphthalenes Pharmacology Chemical synthesis Radioligand Assay Structure-Activity Relationship Dogs Vas Deferens Urethra In vivo Receptors Adrenergic alpha-1 Drug Discovery medicine Animals Receptor Aorta Active metabolite Sulfonamides Chemistry Imidazoles Vas deferens Muscle Smooth Rats medicine.anatomical_structure Molecular Medicine Female Adrenergic alpha-1 Receptor Agonists Rabbits Spleen Phenylpropanolamine Muscle Contraction medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 47:3220-3235 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm030551a |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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