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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. 2004
Robert J Altenbach, and
Albert Khilevich, and
Teodozyj Kolasa, and
Jeffrey J Rohde, and
Pramila A Bhatia, and
Meena V Patel, and
Xenia B Searle, and
Fan Yang, and
William H Bunnelle, and
Karin Tietje, and
Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
Steven A Buckner, and
Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
John C Cain, and
Chae H Kang, and
Lynne M Ireland, and
Tracy L Carr, and
Thomas R Miller, and
Arthur A Hancock, and
Masaki Nakane, and
Timothy A Esbenshade, and
Michael E Brune, and
Alyssa B O'Neill, and
Donna M Gauvin, and
Sweta P Katwala, and
Mark W Holladay, and
Jorge D Brioni, and
James P Sullivan
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA. Robert.j.altenbach@abbott.com
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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Albert Khilevich, and
Teodozyj Kolasa, and
Jeffrey J Rohde, and
Pramila A Bhatia, and
Meena V Patel, and
Xenia B Searle, and
Fan Yang, and
William H Bunnelle, and
Karin Tietje, and
Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
Steven A Buckner, and
Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
John C Cain, and
Chae H Kang, and
Lynne M Ireland, and
Tracy L Carr, and
Thomas R Miller, and
Arthur A Hancock, and
Masaki Nakane, and
Timothy A Esbenshade, and
Michael E Brune, and
Alyssa B O'Neill, and
Donna M Gauvin, and
Sweta P Katwala, and
Mark W Holladay, and
Jorge D Brioni, and
James P Sullivan
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Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
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Rodger Henry, and
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Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
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Arthur A Hancock, and
Masaki Nakane, and
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Meena V Patel, and
Xenia B Searle, and
Fan Yang, and
William H Bunnelle, and
Karin Tietje, and
Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
Steven A Buckner, and
Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
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Masaki Nakane, and
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Jeffrey J Rohde, and
Pramila A Bhatia, and
Meena V Patel, and
Xenia B Searle, and
Fan Yang, and
William H Bunnelle, and
Karin Tietje, and
Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
Steven A Buckner, and
Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
John C Cain, and
Chae H Kang, and
Lynne M Ireland, and
Tracy L Carr, and
Thomas R Miller, and
Arthur A Hancock, and
Masaki Nakane, and
Timothy A Esbenshade, and
Michael E Brune, and
Alyssa B O'Neill, and
Donna M Gauvin, and
Sweta P Katwala, and
Mark W Holladay, and
Jorge D Brioni, and
James P Sullivan
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Albert Khilevich, and
Teodozyj Kolasa, and
Jeffrey J Rohde, and
Pramila A Bhatia, and
Meena V Patel, and
Xenia B Searle, and
Fan Yang, and
William H Bunnelle, and
Karin Tietje, and
Erol K Bayburt, and
William A Carroll, and
Michael D Meyer, and
Rodger Henry, and
Steven A Buckner, and
Jane Kuk, and
Anthony V Daza, and
Ivan V Milicic, and
John C Cain, and
Chae H Kang, and
Lynne M Ireland, and
Tracy L Carr, and
Thomas R Miller, and
Arthur A Hancock, and
Masaki Nakane, and
Timothy A Esbenshade, and
Michael E Brune, and
Alyssa B O'Neill, and
Donna M Gauvin, and
Sweta P Katwala, and
Mark W Holladay, and
Jorge D Brioni, and
James P Sullivan
August 1993,
Journal of medicinal chemistry,
