Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Abstract

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...

Multifunctional Drugs for Head Injury

“…134 -136 It is thought that the compound, which does not bind to the cannabinoid receptor, has a number of neuroprotective effects, including acting as an NMDA receptor antagonist, 137 a free radical scavenger and antioxidant, 138 and an inhibitor of cytokine TNF-␣. 139 Specifically, the dexanabinol molecule readily crosses the blood-brain barrier and weakly blocks NMDA receptors by interacting with a site close to, but distinct from, that of uncompetitive NMDA antagonists.…”

“…139 Specifically, the dexanabinol molecule readily crosses the blood-brain barrier and weakly blocks NMDA receptors by interacting with a site close to, but distinct from, that of uncompetitive NMDA antagonists. 137 Accordingly, it is able to provide the therapeutic benefits of uncompetitive NMDA-receptor antagonists without the adverse psychotropic effects associated with this class of compounds. 134 By blocking the NMDA receptor, it attenuates calcium influx and thus reduces the likelihood of calcium-triggered autodestruction.…”

Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells

“…Even compounds with no or very low agonistic activity at the CB receptors decreased the cell viability after four days of exposure (Fig 1c). HU 211, the enantiomer of HU 210, lacking activity at CB receptors but acting as a glutamate NMDA receptor antagonist (Feigenbaum et al 1989), also showed a potent cytotoxic effect on P19 EC cell viability with an apparent IC 50 of 0.63 µM using the calcein-AM assay. CBD, a non-psychoactive constituent of the plant Cannabis sativa with low affinity for the CB 1 receptor but behaving as an inverse agonist at the CB 2 receptor (Thomas et al 2007), decreased the P19 cell viability with apparent IC 50 value of 14 µM (Fig.…”

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

“…This compound was found to exhibit pharmacological properties characteristic of a noncompetitive NMDA-receptor antagonist (77,78). HU-211 also blocks tumornecrosis factor synthesis and has antioxidant properties, inhibiting release of ROS (79)(80)(81).…”