Journal of Medicinal Chemistry p. 827 - 833 (1989)
Update date:2022-07-29
Topics:
Ornstein, Paul L.
Schaus, John M.
Chambers, John W.
Huser, Diane L.
Leander, J. David
et al.
We recently prepred a series of 3- and 4-(phosphonoalkyl)pyridine- and piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors.NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia.The compounds prepared were evaluated for their ability to displace <3H>CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists).Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced <3H>CPP binding with IC 50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively.The rest of the compounds prepared were weakly active or inactive in these assays.The pattern of activity observed for this series parallels that observed for the acyclic series of ω-phosphono-α-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive.Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.
View MoreContact:+86-25-52346955
Address:199,JIANYE ROAD,NANJING,CHINA
website:http://www.amadischem.com
Contact:86-571-89925085
Address:Watts Cosine.No.166.Xiangmao Road.
Tianjin Chemsyntech Chemical Co., Ltd
Contact:+86-22-60872258
Address:Haitai green industry base in Tianjin, K1,5-601
Yangzhou Zhongbao Pharmaceutical Co.,Ltd
Contact:+86-514-88290838
Address:Jiangsu Baoying county economic develpment zone in baoying avenue91
website:http://www.uvchemkleys.com
Contact:+86 21 3868 0172
Address:RM-1203, Ziguang Building, #341 Shangcheng Road, Pudong Dist, Shanghai
Doi:10.1016/S0277-5387(00)80136-9
(1986)Doi:10.1021/om00154a001
(1987)Doi:10.1134/S1070363213080136
()Doi:10.1007/BF00810059
(1987)Doi:10.1021/ol802409h
(2009)Doi:10.1039/P29880001157
(1988)