(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A Potent New Neuroprotectant Which Blocks N-Methyl-D-Aspartate Responses

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-08, Vol.38 (16), p.3138-3145
Main Authors: Chenard, B. L, Bordner, J, Butler, T. W, Chambers, L. K, Collins, M. A, De Costa, D. L, Ducat, M. F, Dumont, M. L, Fox, C. B
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Death - drug effects
Cells, Cultured
Genes, fos - drug effects
Glutamatergic system (aspartate and other excitatory aminoacids)
Hippocampus - cytology
Hippocampus - drug effects
Male
Medical sciences
Mice
N-Methylaspartate - antagonists & inhibitors
N-Methylaspartate - pharmacology
Nerve Degeneration - drug effects
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Rats
Structure-Activity Relationship
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Summary:(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00016a017