title: Separation of cannabinoid receptor affinity and efficacy in delta-8-tetrahydrocannabinol side-chain analogues.
abstract: 1. The activities of a number of side-chain analogues of delta-8-tetrahydrocannabinol (Delta(8)-THC) in rat cerebellar membrane preparations were tested. 2. The affinities of each compound for the CB(1) receptor were compared by their respective abilities to displace [(3)H]-SR141716A and their efficacies compared by stimulation of [(35)S]-GTPgammaS binding. 3. It was found that the affinities varied from 0.19+/-0.03 nM for 3-norpentyl-3-[6'-cyano,1',1'-dimethyl]hexyl-Delta(8)-THC to 395+/-66.3 nM for 5'-[N-(4-chlorophenyl)]-1',1'-dimethyl-carboxamido-Delta(8)-THC. 4. The efficacies of these compounds varied greatly, ranging from the very low efficacy exhibited to acetylenic compounds such as 1'-heptyn-Delta(8)-THC and 4'-octyn-Delta(8)-THC to higher efficacy compounds such as 5'-(4-cyanophenoxy)-1',1'-dimethyl-Delta(8)-THC and 5'-[N-(4-aminosulphonylphenyl)]-1',1' dimethyl-carboxamido Delta(8)-THC. All agonist activities were antagonized by the CB(1)-selective antagonist SR141716A. 5. It was found that a ligand's CB(1) affinity and efficacy are differentially altered by modifications in the side-chain. Decreasing the flexibility of the side-chain reduced efficacy but largely did not alter affinity. Additionally, the positioning of electrostatic moieties, such as cyano groups, within the side-chain also has contrasting effects on these two properties. 6. In summary, this report details the characterization of a number of novel Delta(8)-THC analogues in rat cerebellar membranes. It provides the first detailed pharmacological analysis of how the inclusion of electrostatic moieties in the side-chain and also how alteration of the side-chain's flexibility may differentially affect a CB(1) cannabinoid receptor ligand's affinity and efficacy.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, VA 23298, USA.
authors.forename: G
authors.initials: G
authors.lastname: Griffin
authors.forename: S
authors.initials: S
authors.lastname: Williams
authors.forename: M M
authors.initials: MM
authors.lastname: Aung
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
authors.forename: M E
authors.initials: ME
authors.lastname: Abood
mesh_terms: D000818:Animals; D016466:CHO Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D003511:Cyclohexanols; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol