3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and nantradol

More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ

Topics: Analgesics; Animals; Anti-Anxiety Agents; Cannabinoid Receptor Agonists; Cannabinoids; Controlled Substances; Cyclohexanols; Dronabinol; Humans; Mental Disorders; Pain; Phenanthridines; Receptor, Cannabinoid, CB1

We investigated interactions between cannabinoid and dopamine receptor systems in ICR mice. Mice were treated with the cannabinoid agonist levonantradol, the D(1) dopamine agonist 6-Br-APB, or the D(2) dopamine agonist quinelorane, or with combinations of these drugs. In addition, the D(1) antagonist SCH23390 was administered both alone and in combination with levonantradol. Two tests were used to evaluate changes in motor function: the immobility (ring stand) test and the catalepsy (bar) test. Levonantradol increased immobility and catalepsy in a dose-dependant manner. Both the D(2) agonist quinelorane and the D(1) agonist 6-Br-APB were able to attenuate the motor dysfunction caused by levonantradol. Administration of the D(1) antagonist SCH23390 enhanced the effects of levonantradol, producing a leftward shift of the log dose-response curve. These results differ from the augmentation by D(2) agonists of the hypoactivity induced by levonantradol in non-human primates [Meschler JP, Clarkson FA, Mathew PJ, Howlett AC, Madras BK. D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates. J Pharmacol Exp Ther 2000;292:952-959], suggesting that conclusions about the interactions between the dopamine and cannabinoid receptor motor systems in rodents may not extend to primates.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analgesics; Animals; Cannabinoids; Cyclohexanols; Dopamine Agonists; Immobilization; Male; Mice; Mice, Inbred ICR; Motor Activity; Phenanthridines; Quinolines

The effects of several nonclassical cannabinoids and the endogenous cannabinoid ligand, anandamide on the lipid ordering of rat brain synaptic plasma membranes (SPM) were examined and compared to delta 9-tetrahydrocannabinol (delta 9-THC). SPM order was determined using fluorescence polarization. All compounds tested affected membrane ordering. delta 9-THC, CP-55,940, CP-55,244 and WIN-55212 decreased lipid ordering in SPM. Some stereospecificity was observed with delta 9-THC and WIN-55212, but not other compounds. Anandamide also decreased lipid order as did its putative precursor, arachidonic acid. In contrast to these compounds, levonantradol increased SPM lipid order. Although all pharmacologically active cannabinoids affect SPM lipid order, potency on this measure does not correlate well with their pharmacological potency. The results of this study suggest that membrane perturbation (either increases or decreases in lipid order) may be a necessary characteristic for cannabinoid pharmacological activity, but it is not a primary or sufficient determinate of action for this class of drugs.

Topics: Analgesics; Animals; Arachidonic Acid; Arachidonic Acids; Benzoxazines; Brain; Cannabinoids; Cyclohexanols; Dronabinol; Endocannabinoids; Male; Membrane Lipids; Morpholines; Naphthalenes; Phenanthridines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Synaptic Membranes

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.

Topics: Action Potentials; Animals; Benzoxazines; Cannabinoids; Cells, Cultured; Cyclohexanols; GTP Phosphohydrolases; GTP-Binding Proteins; Hippocampus; Membrane Potentials; Morpholines; Naphthalenes; Neurons; Phenanthridines; Potassium; Rats; Receptors, Cannabinoid; Receptors, Drug; Receptors, GABA-B