title: Assessment of structural commonality between tetrahydrocannabinol and anandamide.
abstract: In order to make further structural comparisons between tetrahydrocannabinol and anandamide, substituents at C1 and C3 of the phenolic ring of tetrahydrocannnabinol were altered. In order to examine the alignment of the phenolic hydroxyl of tetrahydrocannnabinol with the hydroxyl group of anandamide, 1-fluoro-1-deoxy-tetrahydrocannnabinol analogs were prepared. These analogs had low affinity for the CB(1) cannabinoid receptor and were considerably less potent than tetrahydrocannnabinol in producing pharmacological effects in mice. These results suggest that these two oxygen moieties do not overlap. Additionally, the fact that a fluorine group can only accept hydrogen bonds suggest that the phenolic oxygen at the C1 position of tetrahydrocannnabinol donates electrons for hydrogen bonding rather than the hydrogen of the hydroxyl group interacting with the receptor. Additionally, substitution of a fluorine for the hydroxyl group at C1 led to analogs with higher affinity for CB(2) than CB(1) cannabinoid receptors, thereby underscoring a fundamental difference in the binding properties of these two receptor subtypes.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA. martinb@hsc.vcu.edu
authors.forename: Billy R
authors.initials: BR
authors.lastname: Martin
authors.forename: Renee G
authors.initials: RG
authors.lastname: Jefferson
authors.forename: Ramona
authors.initials: R
authors.lastname: Winckler
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crocker
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Raj K
authors.initials: RK
authors.lastname: Razdan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D001095:Arachidonic Acids / Q000737:chemistry* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D013759:Dronabinol / Q000737:chemistry* / Q000494:pharmacology; D063388:Endocannabinoids; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; C078814:anandamide