Synthesis and Structure−Activity Relationships of 6,7-Benzomorphan Derivatives as Antagonists of the NMDA Receptor−Channel Complex

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Abstract
We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-d-aspartate (NMDA) receptor−channel complex in vitro and in vivo. The ability of the compounds to displace [3H]MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the μ opioid receptor. Examination of structure−activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (−)-1R,9β,2‘‘S-enantiomers exhibited a higher affinity for the NMDA receptor−channel complex than for the μ opioid receptor. The aromatic hydroxy function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2‘-position to the 3‘-position significantly increased the affinity for the NMDA receptor−channel complex and considerably reduced the affinity for the μ opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr·HCl [(2R)-[2α,3(R*),6α]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations.