J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors
J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors
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DOI：
10.1016/s0968-0896(99)00177-7
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发表时间：
1999-11-01
影响因子：
3.5
通讯作者：
Tomimoto, K
中科院分区：
文献类型：
--
作者：
Mitsuya, M;Mase, T;Tomimoto, K
合成了一类新的4-乙酰氨基哌啶衍生物，并研究了其对人毒蕈碱受体亚型的选择性。将适当长度的烃链引入外消旋N-（哌啶-4-基）-2-环丁基-2-羟基-2-苯基乙酰胺平台的哌啶氮中，赋予人毒蕈碱M-3受体超过M-2受体的高达70倍的选择性。随后的合成衍生化产生了高效的M-3受体拮抗剂，其对M-3的选择性大于M-2受体的两个数量级，从中选择了类似物4 r。4 r的两种对映异构体的制备导致鉴定（2 R）-N-[1-（4-甲基-3-戊烯基）哌啶-4-基]-2-环戊基-2-羟基-2-苯基乙酰胺（J-104129，（R）-4r），其对Mg受体（Ki = 4.2 nM）的选择性是对M-2受体（Ki = 490 nM）的120倍。在离体大鼠气管中，（R）-4r有效且特异性地拮抗乙酰胆碱（ACh）诱导的反应，K-B值为3.3 nM。在离体大鼠组织测定（50倍）和麻醉大鼠（> 250倍）中也观察到高度亚型选择性特征。J-104129（（R）-4r）经口给药可拮抗ACh诱导的大鼠支气管收缩，ED 50值为0.58 mg/kg。因此，J-104129（（R）-4r）可有效促进支气管扩张治疗阻塞性气道疾病。(C)1999 Elsevier Science Ltd.保留所有权利。
A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M-3 receptors over M-2 receptors. Subsequent synthetic derivatizations resulted in highly potent M-3 receptor antagonists with selectivity greater than two orders of magnitude for M-3 over M-2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for Mg receptors (K-i = 4.2 nM) over M-2 receptors (K-i = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K-B value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease. (C) 1999 Elsevier Science Ltd. All rights reserved.