Pharmacological characterization of Ro 63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist

J Pharmacol Exp Ther. 2002 Sep;302(3):940-8. doi: 10.1124/jpet.102.034322.

Abstract

Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [(3)H]dizocilpine ((3)H-MK-801) binding in a biphasic manner with IC(50) values of 0.002 and 97 microM for the high- and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C + NR2B subunits with an IC(50) of 0.003 microM and those containing NR1C + NR2A subunits with an IC(50) of >100 microM, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C + NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC(50) values of 0.68 and 0.06 microM, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED(50) = 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED(50) of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.

MeSH terms

  • Acoustic Stimulation
  • Algorithms
  • Animals
  • Anticonvulsants / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / ultrastructure
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Electrophysiology
  • Excitatory Amino Acid Antagonists / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • In Vitro Techniques
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / pathology
  • Macaca fascicularis
  • Male
  • Mice
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Phenols / metabolism
  • Phenols / pharmacokinetics
  • Phenols / pharmacology*
  • Piperidines / metabolism
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Psychomotor Performance / drug effects
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Seizures / prevention & control
  • Vacuoles / drug effects
  • Xenopus

Substances

  • Anticonvulsants
  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Phenols
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Ro 631908