CP-101,606, a potent neuroprotectant selective for forebrain neurons.
The neuroprotective activity of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606), an N-methyl-D-aspartate (NMDA) receptor antagonist structurally similar to ((+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-++ +piperidineethanol (ifenprodil), was investigated in neurons in primary culture. CP-101,606 potently and efficaciously protected hippocampal neurons from glutamate toxicity but was > 900-fold less effective for cerebellar granule neurons. The neuroprotective activity in the hippocampal neurons is mediated through a high affinity binding site distinct from the agonist and thienylcyclohexylpiperidine (TCP) binding sites of the NMDA receptor. Autoradiography indicates the CP-101,606 binding site is localized in forebrain, most notably in hippocampus and the outer layers of cortex. The functional selectivity for hippocampal neurons, forebrain localization of binding sites, and structural relation to ifenprodil suggest that CP-101,606 is an NMDA antagonist highly selective for NR2B subunit containing receptors.
Menniti
F
F
Pfizer Inc., Central Research Division, Groton, CT 06340, USA. mennif@pfizer.com
Chenard
B
B
Collins
M
M
Ducat
M
M
Shalaby
I
I
White
F
F
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D005998:Glycine / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D016548:Prosencephalon / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C053672:selfotel; C095106:traxoprodil mesylate; D005998:Glycine