In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist.

Abstract The analgesic activity and side effect liabilities of a novel NR2B antagonist, 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (HON0001) were investigated. HON0001 inhibited [ 3 H]MK-801 binding to rat brain membranes in a biphasic manner, with IC 50 values of 54.68 ± 4.96 nM and 46.48 ± 5.85 μM for high- and low-affinity sites, respectively. HON0001 inhibited [ 3 H]ifenprodil binding to membranes of rat cerebral cortex with an IC 50 value of 57.01 ± 3.4 nM, consistent with the results obtained for high-affinity sites of [ 3 H]MK-801 binding. HON0001 exhibited no or negligible affinity for other receptors, transporters and ion channels, while HON0001 had a moderate agonistic activity at μ-opioid receptors and affinity for dopamine D 1 receptors. HON0001 exhibited an analgesic effect in carrageenan-induced mechanical hyperalgesia and in the Seltzer model of partial sciatic nerve ligation following oral administration. In contrast, unlike MK-801, HON0001 did not affect spontaneous locomotor activity, rotarod performance and step-through latency in a passive avoidance task even at doses much higher than antinociceptive doses. HON0001 exhibited excellent brain penetration with a brain-to-plasma ratio of 34.5. These findings show that HON0001 is an orally active NR2B antagonist and that it may be useful for treating patients with neuropathic and other conditions without causing the side effects often observed with currently available non-subtype selective NMDA receptor antagonists.