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

• Published in: Journal of medicinal chemistry Vol. 38; no. 16; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.08.1995; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cell Death - drug effects; Cells, Cultured; Chemistry, Medicinal; Genes, fos - drug effects; Glutamatergic system (aspartate and other excitatory aminoacids); Hippocampus - cytology; Hippocampus - drug effects; Life Sciences & Biomedicine; Male; Medical sciences; Mice; N-Methylaspartate - antagonists & inhibitors; N-Methylaspartate - pharmacology; Nerve Degeneration - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; ACID-INDUCED SEIZURES; GLUTAMATE NEUROTOXICITY; ANTAGONIST; NMDA RECEPTORS; C-FOS; FOCAL CEREBRAL-ISCHEMIA; SL-82.0715; IFENPRODIL; RAT-BRAIN; BINDING; Aminoalcohol; Rat; Nitrogen heterocycle; Rodentia; Central nervous system; Neuroprotective agent; Glutamate receptor; Propanol derivatives; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Piperidine derivatives; Threo stereoisomer; Antagonist; NMDA receptor; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00016a017

(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 al adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on the 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 al adrenergic affinity (IC50 similar to 20 mu M) 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.