(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol:  A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol

(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol:  A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was e...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 41; no. 7; pp. 1172 - 1184
Main Authors: Butler, Todd W, Blake, James F, Bordner, Jon, Butler, Paul, Chenard, Bertrand L, Collins, Mary A, DeCosta, Debra, Ducat, Mary J, Eisenhard, Michael E, Menniti, Frank S, Pagnozzi, Martin J, Sands, Steven B, Segelstein, Barbara E, Volberg, Walter, White, W. Frost, Zhao, Dayao
Format: Journal Article
Language:English
Published: Washington, DC American Chemical Society 26-03-1998
Subjects:
Animals
Biological and medical sciences
Chromans - chemical synthesis
Chromans - pharmacology
Dose-Response Relationship, Drug
Glutamatergic system (aspartate and other excitatory aminoacids)
Male
Medical sciences
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Structure-Activity Relationship
Enantiomer(+)
Rat
Rodentia
Oral administration
Neuroprotective agent
Glutamate receptor
Oxygen heterocycle
In vitro
Dose activity relation
In vivo
Vertebrata
Mammalia
Structure activity relation
Animal
Piperidine derivatives
Bicyclic compound
Phenols
Subcutaneous administration
Aromatic compound
Antagonist
NMDA receptor
Chemical synthesis
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Summary:(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptorcis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.
Bibliography:ark:/67375/TPS-LCB3RL1G-9
istex:846CB3721B096DDACC6DFEC4788DD92DBF23881F
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9707986