Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-A'-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotypy and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.The enantiomers of the synthetic cannabinoid 7-hydroxy-A6-tetrahydrocannabinol 1,1-dimethylheptyl homolog have recently been described (1, 2). The (-)-(3R,4R) enantiomer, code-named HU-210 ( Fig. 1), is a highly potent cannabimimetic compound (-80 times more active than &1-tetrahydrocannabinol, the active component of hashish); the (+)-(3S,4S) enantiomer (code-named HU-211) (Fig. 1) is inactive as a cannabimimetic, even at doses several thousand times higher than the ED50 of HU-210 as assayed in a number of tests (2). In characterizing the drug profile of the nonpsychotropic (+) enantiomer HU-211, we noted a striking similarity between its pharmacological, autonomic, and behavioral effects and those of noncompetitive N-methyl-D-aspartate (NMDA) antagonists over a wide range of activities (including stereotypy, locomotor hyperactivity, and tachycardia). This similarity suggested that HU-211 might be functionally active as an NMDA-receptor antagonist. To explore the action of HU-211 and its interaction with specific receptors in the brain, we conducted both pharmacological experiments and binding studies. MATERIALS AND METHODS 3H-labeled N-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP)(40 Ci/mmol; 1 Ci = 37 GBq; >98% pure) was purchased from the Israel Nuclear Center (Negev, Israel). L-Glutamate and glycine were from Sigma; D-(-)-2-amino-5-phosphonovaleric acid (AP-5) and NMDA were from Cambridge Research Biochemicals (Harston, U.K.). HU-211 and HU-210 were synthesized as described (1). Both enantiomers melt at 140-141°C and have identical IR and NMR spectra. administration and tested 60 min after injection. Locomotor hyperactivity was measured as body displacement over 7-cm squares, movement from one square to the next constituting a score of 1. This movement was independently assessed by three trained observers.Heart rate measured over 75 min was determined by the standard transducer-amplifier-recorder technique, and respiratory frequency was visually observed by three trained independent observers with a very high meter-rater correlation. Tremor and seizure were monitored on a platform mounted on four spring-coils. Any vibration of the platform was transduced into an electrical input to an amplifer and then to an osci...

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Excitatory amino acids in the CNS are involved in phenomena as disparate as synaptic plasticity and excitotoxicity [l].