SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 6,7-BENZOMORPHAN DERIVATIVES AS ANTAGONISTS OF THE NMDA RECEPTOR-CHANNEL COMPLEX

We have synthesized a series of stereoisomeric 6,7-benzomorphan deriva tives with modified N-substituents and determined their ability to ant agonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vi tro and in vivo. The ability of the compounds to displace [H-3]_ MK-80 1 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 mu opioid receptor. Examination of s tructure-activity relationships showed that the absolute stereochemist ry is critically important for differentiating these two effects. (-)- 1R,9 beta,2''S-enantiomers exhibited a higher affinity for the NMDA re ceptor-channel complex than for the mu opioid receptor. The aromatic h ydroxy function was also found to influence the specificity of the com pounds. Shift of the hydroxy group from the 2'-position to the 3'-posi tion significantly increased the affinity for the NMDA receptor-channe l complex and considerably reduced the affinity for the mu opioid rece ptor. From this series of 6,7-benzomorphan derivatives, the compound 1 5cr . HCl [(2R)-[2 alpha,3(R),6 1,2,3,4,5,6-hexahydro-3-(2-methoxypro pyl)-6,11,11- trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride] w as chosen as the optimum candidate for further pharmacological investi gations.