Abstract
Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selectiveN-methyl-d-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [3H]dizocilpine (3H-MK-801) binding in a biphasic manner with IC50 values of 0.002 and 97 μM for the high- and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopusoocytes containing NR1C + NR2B subunits with an IC50 of 0.003 μM and those containing NR1C + NR2A subunits with an IC50 of >100 μM, 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 IC50 values of 0.68 and 0.06 μM, 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 (ED50 = 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 ED50 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.
Footnotes
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DOI: 10.1124/jpet.102.034322
- Abbreviations:
- Ro 63-1908
- 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol
- NMDA
- N-methyl-d-aspartate
- CNS
- central nervous system
- NR
- NMDA receptor
- CP 101,606
- (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
- Ro 25-6981
- (1R,2S)-4-[3-(4-benzyl-piperidin-1-yl)-1-hydroxy-2-methyl-propyl]-phenol
- MK-801
- dizocilpine
- TCP
- [1-(2-thienyl)cyclohexyl]piperidine
- Ro 04–5595
- 1-(4-chlorophenyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinolin
- OGD
- oxygen-glucose deprivation
- MORO
- mouse Roche only (albino)
- MCA
- middle cerebral artery
- ANOVA
- analysis of variance
- Received March 5, 2002.
- Accepted April 29, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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