193357-64-1Relevant academic research and scientific papers
4-hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: A novel, potent, and selective NR1/2B NMDA receptor antagonist
Zhou, Zhang-Lin,Cai, Sui Xiong,Whittemore, Edward R.,Konkoy, Christopher S.,Espitia, Stephen A.,Tran, Minhtam,Rock, David M.,Coughenour, Linda L.,Hawkinson, Jon E.,Boxer, Peter A.,Bigge, Christopher F.,Wise, Lawrence D.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
, p. 2993 - 3000 (1999)
A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 μM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for α1-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a ~25-fold increase in NR1A/2B potency (IC50 = 0.025 μM). p-Methyl substitution on the benzyl ring (10b) produced a ~3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for α1 receptors and reduction in inhibition of K+ channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4- hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.
4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
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, (2011/05/18)
PCT No. PCT/US96/20872 Sec. 371 Date Sep. 16, 1998 Sec. 102(e) Date Sep. 16, 1998 PCT Filed Dec. 20, 1996 PCT Pub. No. WO97/23216 PCT Pub. Date Jul. 3, 1997Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 4-substituted piperidine analogs are selective active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, psychosis, anxiety, migraine headaches, glaucoma, CMV retinitis, aminoglycoside antibiotics-induced hearing loss, convulsions, chronic pain, opioid tolerance or withdrawal, urinary incontinence or neurodegenerative disorders, such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease are described.
