RT Journal Article
SR Electronic
T1 Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-Selective<em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Antagonist
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 940
OP 948
DO 10.1124/jpet.102.034322
VO 302
IS 3
A1 R. Gill
A1 A. Alanine
A1 A. Bourson
A1 B. Buttelmann
A1 G. Fischer
A1 M.-P. Heitz
A1 J. N. C. Kew
A1 B. Levet-Trafit
A1 H.-P. Lorez
A1 P. Malherbe
A1 M.-T. Miss
A1 V. Mutel
A1 E. Pinard
A1 S. Roever
A1 M. Schmitt
A1 G. Trube
A1 R. Wybrecht
A1 R. Wyler
A1 J. A. Kemp
YR 2002
UL http://jpet.aspetjournals.org/content/302/3/940.abstract
AB 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 &gt;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. The American Society for Pharmacology and Experimental Therapeutics