Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum

Abstract

1 The e ect of allosteric regulators on the binding a nity of a number of cannabinoid receptor ligands of varying e cacy in the rat cerebellum was investigated. 2 Radioligand ([ 3 H]-SR141716A) competition curves were constructed in the presence or absence of sodium ions, magnesium ions and guanine nucleotides. 3 It was found that the presence of these allosteric regulators did not a ect the a nity of the two antagonists used but did cause a signi®cant decrease in the a nity of full and partial agonists. 4 This reduction in a nity ranged from a 3.67 fold rightward shift of the displacement curve of a mixed agonist/antagonist (3-(6-cyano-2-hexynyl)-delta-8-tetrahydrocannabinol-O-823) to a 38 fold rightward shift for 3-(1,1-dimethyl-6-dimethylcarboxamide)-delta-8-tetrahydrocannabinol (O-1125), a full agonist. 5 In summary, the results of this study suggest a simple method for the inference of functional data using the classical radioligand binding assay.

Pharmacological Properties of Cannabinoid Receptors in the Avian Brain: Similarity of Rat and Chicken Cannabinoid1 Receptor Recognition Sites and Expression of Cannabinoid2 Receptor‐Like Immunoreactivity in the Embryonic Chick Brain

“…The rates of association and dissociation, K D values and inhibition by a variety of cannabinoid ligands were very similar in membranes from chicken and rat brain. In addition, the shift to the right of the inhibition of [ 3 H]SR 141716A binding by CP 55,940 in the presence of non-hydrolysable GTP analogues is in line with previous studies in the rat brain (Griffin et al 1999a;Houston & Howlett 1998), and would suggest that in the chicken membranes, the cannabinoid 1 receptors retain functional coupling to their G-proteins.…”

“…The simplest explanation for this difference is that in the present study, a greater proportion of receptor recognition sites are in a low-affinity state. However, evidence of co-operative receptor-ligand interactions for G-protein coupled receptors (see Chidiac 1998), the importance of the assay ion composition (see Houston & Howlett 1998;Griffin et al 1999a) and the fact that [ 3 H]SR 141716A acts as an inverse agonist rather than a true antagonist (Pan et al 1998) are all likely to affect n H values, so it is wise not to overinterpret this finding. In any case, whatever the explanation, the important findings are that the GTP-analogues affect the CP 55,940 inhibition curve in a similar manner in both species, and that the pharmacological properties of the rat and chicken cannabinoid 1 receptor recognition sites, when assayed under the same conditions, are rather similar.…”

Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB 1

“…2B), which would be expected for an allosteric ligand with positive cooperativity with respect to agonist binding. Sodium, a wellknown allosteric antagonist for many GPCRs, including CB 1 (26,27), also further enhances this observed potency (Fig. S2).…”

Synthesis of Fatty Acid Amides of Catechol Metabolites that Exhibit Antiobesity Properties

“…Calculated pK i values of our compounds are similar to that of endogenous anandamide, using the same labeled CB 1 ligand ([ and similar experimental conditions, but lower than those of synthetic ligands WIN55212-2 and SR141716. [27] We also tested the efficacy of compounds 5, 6, 8, and 11 for PPAR-a by the transient transfection and luciferase reporter assay. We used OEA and AEA as positive and negative controls, respectively.…”