Kaiser C, Audia V H, Carter J P, McPherson D W, Waid P P, Lowe V C, Noronha-Blob L
Scios Nova Inc., Baltimore, Maryland 21224-6522.
J Med Chem. 1993 Mar 5;36(5):610-6. doi: 10.1021/jm00057a010.
A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. The objective of this study was to derive new antimuscarinic agents with potential utility in treating urinary incontinence associated with bladder muscle instability. These compounds were examined for M1, M2, and M3 muscarinic receptor selectivity in isolated tissue assays and for in vivo effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. Potency and selectivity in these assays were influenced most notably by the nature of the substituent group on the terminal nitrogen of the piperazine moiety. Benzyl substitution was particularly advantageous in producing compounds with functional M3 receptor (smooth muscle) and bladder selectivity; it provided several candidates for clinical study. In vivo, 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (24) demonstrated 11- and 37-fold separations in its effect on bladder function versus mydriatic and salivation responses, respectively. The corresponding 2-chlorobenzyl derivative 25 was more than 178-fold selective for M3 versus M1 and M2 muscarinic receptors. 3-(4-Benzylpiperazinyl)-1,1-diphenyl-1-hydroxy-2-propanone (51) was 18-fold selective for M3 versus M1 and 242-fold selective for M3 versus M2 receptors. It was also selective in guinea pigs, where it displayed 20- and 41-fold separations between bladder function and effect on mydriasis and salivation, respectively. In general, the results of this study are consistent with the proposition that the described piperazinylpropanones interact with muscarcinic receptors in a hydrogen-bonded form that presents a conformation similar to that apparently adopted by classical antimuscarinic agents.
报道了一类具有抗毒蕈碱活性的新型取代1-苯基-3-哌嗪基-2-丙酮。作为该类结构-活性关系研究的一部分，研究了各种结构修饰，特别是涉及1位取代和哌嗪末端氮取代的修饰。本研究的目的是获得具有潜在效用的新型抗毒蕈碱药物，用于治疗与膀胱肌肉不稳定相关的尿失禁。在离体组织试验中检测了这些化合物对M1、M2和M3毒蕈碱受体的选择性，以及对豚鼠膀胱收缩、瞳孔散大及唾液分泌的体内效应。这些试验中的效力和选择性最显著地受到哌嗪部分末端氮上取代基性质的影响。苄基取代在产生具有功能性M3受体（平滑肌）和膀胱选择性的化合物方面特别有利；它提供了几个可供临床研究的候选物。在体内，3-(4-苄基-哌嗪基)-1-环丁基-1-羟基-1-苯基-2-丙酮（24）对膀胱功能的影响与对瞳孔散大和唾液分泌反应的影响分别有11倍和37倍的差异。相应的2-氯苄基衍生物25对M3受体相对于M1和M2毒蕈碱受体的选择性超过178倍。3-(4-苄基哌嗪基)-1,1-二苯基-1-羟基-2-丙酮（51）对M3受体相对于M1受体的选择性为18倍，对M3受体相对于M2受体的选择性为242倍。它在豚鼠中也具有选择性，在豚鼠中其膀胱功能与对瞳孔散大和唾液分泌的影响之间分别有20倍和41倍的差异。总体而言，本研究结果与以下观点一致：所述哌嗪基丙酮以氢键形式与毒蕈碱受体相互作用，其构象与经典抗毒蕈碱药物明显采用的构象相似。
