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

被引：7

作者：

Altenbach, RJ ^{[1
]}

Khilevich, A ^{[1
]}

Kolasa, T ^{[1
]}

Rohde, JJ ^{[1
]}

Bhatia, PA ^{[1
]}

Patel, MV ^{[1
]}

Searle, XB ^{[1
]}

Yang, F ^{[1
]}

Bunnelle, WH ^{[1
]}

Tietje, K ^{[1
]}

Bayburt, EK ^{[1
]}

Carroll, WA ^{[1
]}

Meyer, MD ^{[1
]}

Henry, R ^{[1
]}

Buckner, SA ^{[1
]}

Kuk, J ^{[1
]}

Daza, AV ^{[1
]}

Milicic, IV ^{[1
]}

Cain, JC ^{[1
]}

Kang, CH ^{[1
]}

Ireland, LM ^{[1
]}

Carr, TL ^{[1
]}

Miller, TR ^{[1
]}

Hancock, AA ^{[1
]}

Nakane, M ^{[1
]}

Esbenshade, TA ^{[1
]}

Brune, ME ^{[1
]}

O'Neill, AB ^{[1
]}

Gauvin, DM ^{[1
]}

Katwala, SP ^{[1
]}

Holladay, MW ^{[1
]}

Brioni, JD ^{[1
]}

Sullivan, JP ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Neurosci Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 12期

关键词：

D O I：

10.1021/jm030551a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (ALAP) 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.

引用

页码：3220 / 3235

页数：16

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