Vol. 302, Issue 3, 940-948, September 2002

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

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

F. Hoffmann-La Roche Ltd., Preclinical Research Basel, CNS Department, Basel, Switzerland

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 [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 Xenopus oocytes 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.