title: Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation.
abstract: CB1 and CB2 cannabinoid receptors can be activated by several different classes of agonists, including cannabinoids such as delta9-tetrahydrocannabinol and 9-nor-9beta-hydroxyhexahydrocannabinol, and eicosanoids such as arachidonylethanolamide. Structure-activity relationship studies have identified potential pharmacophoric elements for binding to cannabinoid receptors by both cannabinoids and eicosanoids. Molecular models have hypothesized conformational, spatial, and pharmacophoric distance requirements based upon radioligand binding data whereby overlap of pharmacophoric elements of the two classes disclose a low energy conformation of arachidonylethanolamide that can occupy the same receptor space as cannabinoid ligands. To test this model, we have developed a novel class of monocyclic and bicyclic alkyl amide cannabinoid receptor ligands. Further, we predicted a spatial conformation for these compounds in a molecular model based on the pharmacophoric and structural requirements for binding to the CB1 cannabinoid receptor.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School Medicine, MO 63104, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Berglund
authors.forename: P R
authors.initials: PR
authors.lastname: Fleming
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: J Y
authors.initials: JY
authors.lastname: Shim
authors.forename: W J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: A C
authors.initials: AC
authors.lastname: Howlett
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000577:Amides; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D011083:Polycyclic Compounds; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D019204:GTP-Binding Proteins