Hong S S, Romstedt K J, Feller D R, Hsu F L, George C, Cupps T L, Lyon R A, Miller D D
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210.
Chirality. 1992;4(7):432-8. doi: 10.1002/chir.530040706.
Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.
最近我们合成了美托咪定的萘类似物，4-[1-(1-萘基)乙基]-1H-咪唑盐酸盐(1)，并发现它在肾上腺素能系统中具有高效能。通过使用酒石酸的异构体实现了这种萘类似物光学异构体的分离。异构体的光学纯度通过使用手性柱的高效液相色谱法测定。通过X射线分析确定(+)-异构体具有S绝对构型。据报道，美托咪定(2)的(+)-异构体是α2-肾上腺素能受体上最具活性的对映体。在豚鼠回肠和人血小板的α1-和α2-肾上腺素能受体系统中，1的光学异构体的生物活性存在定性和定量差异。(+)-(S)-1而非(-)-(R)-1是回肠中α2介导反应的选择性激动剂，而(-)-(R)-1作为α2介导的血小板聚集抑制剂比(+)-(S)-1更有效。
