Elworthy T R, Ford A P, Bantle G W, Morgans D J, Ozer R S, Palmer W S, Repke D B, Romero M, Sandoval L, Sjogren E B, Talamás F X, Vazquez A, Wu H, Arredondo N F, Blue D R, DeSousa A, Gross L M, Kava M S, Lesnick J D, Vimont R L, Williams T J, Zhu Q M, Pfister J R, Clarke D E
Roche Bioscience, Palo Alto, California 94304-1397, USA.
J Med Chem. 1997 Aug 15;40(17):2674-87. doi: 10.1021/jm970166j.
Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
通过体外功能筛选，新型芳基哌嗪被鉴定为α1 -肾上腺素能受体（AR）亚型选择性拮抗剂。3 - [4 -（邻位取代苯基）哌嗪 - 1 - 基]丙胺用N，N - 二甲基邻氨基苯甲酰胺、烟酰胺以及喹啉、1,8 - 萘啶、吡唑并[3,4 - b]吡啶、异恶唑并[3,4 - b]吡啶、咪唑并[4,5 - b]吡啶和吡唑并[1,5 - a]嘧啶的羧酰胺进行衍生化。兔膀胱颈条带被用作预测人体下尿路拮抗作用的检测方法。大鼠主动脉环被用作测试拮抗剂的“阴性筛选”。与α1 - ARs的结合对拮抗剂芳基哌嗪部分的大小和电子特征相对敏感，并且对杂芳基羧酰胺侧链上的这些特征具有耐受性。利用这些结构 - 亲和力研究结果，制备了在人下尿路中普遍存在的α1 - AR亚型上具有纳摩尔亲和力（pA2值分别为8.8、10.7、9.3和9.9）且对α1D - AR具有2 - 3个数量级选择性的烟酰胺（如13ii和25x）和吡唑并[3,4 - b]吡啶（如37f和37y）配体。
