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

Gill, R.; Alanine, A.; Bourson, A.; Buttelmann, B.; Fischer, G.; Heitz, M.-P.; Kew, J.N.C.; Levet-Trafit, B.; Lorez, H.-P.; Malherbe, P.; Miss, M.-T.; Mutel, V.; Pinard, E.; Roever, S.; Schmitt, M.; Trube, G.; Wybrecht, R.; Wyler, R.; Kemp, J.A.

Journal of Pharmacology and Experimental Therapeutics 302(3): 940-948


ISSN/ISBN: 0022-3565
PMID: 12183650
DOI: 10.1124/jpet.102.034322
Accession: 046968147

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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.