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 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 mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (-)-1R,9 beta,2"S-enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the mu 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 mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-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.
Grauert
M
M
Department of Medicinal Chemistry, Boehringer Ingelheim, KG, Ingelheim am Rhein, Federal Republic of Germany.
Bechtel
W D
WD
Ensinger
H A
HA
Merz
H
H
Carter
A J
AJ
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D004090:Dihydromorphine / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D001575:Benzomorphans; D007473:Ion Channels; D009022:Morphine Derivatives; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D004090:Dihydromorphine