Journal of Medicinal Chemistry p. 3693 - 3699 (1993)
Update date:2022-08-03
Topics:
Van Wijngaarden
Hamminga
Van Hes
Standaar
Tipker
Tulp
Mol
Olivier
De Jonge
On the basis of the structures of ondansetron and GR 65,630, its ring- opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5- HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1- yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (K(i) = 0.19 nM), a weak affinity for σ-receptors (K(i) = 340 nM), muscarine M1 receptors (K(i) = 910 nM), and 5-HT4 receptors (K(i) = 960 nM) and no affinity (K(i) ≥ 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.
View MoreJiangxi Province Bethel Pharmaceutical Co., Ltd.
Contact:+86-795-259 3456 ,+86-15957688008 13566650571
Address:Huangjindui Chemical Park, Shanggao County ,Yichun city,Jiangxi Province
Shandong LuZhou Amino Acid Co., Ltd
Contact:86-539-2218025
Address:yishui economic and technical development zone zhenxing south road
Shanghai shibo Chemical Co., Ltd
Contact:+86-021-60753516
Address:688 Qiushi Road, Jinshan High-tech Park, Shanghai, China,201512
website:http://www.hybio.com.cn
Contact:+86 755 26588093
Address:No.9 Linkong West Street, Hengdian Street, Huangpi District, Wuhan City, China.
Contact:0086-22-2822 1962 / 2822 1963
Address:B-808, No. 1, North-South Street, Hexi District,
Doi:10.1016/S0040-4039(00)99549-2
(1989)Doi:10.1016/j.jphotochem.2010.05.005
(2010)Doi:10.1021/jo00300a032
(1990)Doi:10.1021/acs.biomac.6b00082
(2016)Doi:10.1039/c0ob01278e
(2011)Doi:10.1021/ja2004158
(2011)