title: Pharmacological and behavioral evaluation of alkylated anandamide analogs.
abstract: Anandamide (arachidonylethanolamide), isolated from porcine brain, has been shown to bind to the cannabinoid receptor and also to produce cannabimimetic activity in pharmacological assays. This study examined structure-activity relationships in alkylated anandamide analogs. The analogs were evaluated for their ability to displace [3H]CP-55,940 in a filtration binding assay using rat brain membranes in the presence and absence of the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF). Behavioral activity was assessed by the ability of the analogs to produce hypomotility and antinociception. Methylations at carbons 2 and 1 produced compounds stable in the absence of PMSF with similar affinities and behavioral activity as anandamide. Addition of larger alkyl groups at these positions or nitrogen methylation reduced receptor affinity and behavioral potency. These results indicate that methylations at specific carbons of anandamide confer stability in vitro.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
authors.forename: I B
authors.initials: IB
authors.lastname: Adams
authors.forename: W
authors.initials: W
authors.lastname: Ryan
authors.forename: M
authors.initials: M
authors.lastname: Singer
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: D R
authors.initials: DR
authors.lastname: Compton
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000478:Alkylation; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003511:Cyclohexanols / Q000378:metabolism / Q000494:pharmacology; D063388:Endocannabinoids; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D002186:Cannabinoids; D003511:Cyclohexanols; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C078814:anandamide