title: Synthesis and CB1 receptor activities of dimethylheptyl derivatives of 2-arachidonoyl glycerol (2-AG) and 2-arachidonyl glyceryl ether (2-AGE).
abstract: Results from a factor analysis and activity studies of commercially available endocannabinoid-type compounds set the starting point for the current study where dimethylheptyl (DMH) analogues of two endocannabinoids, 2-arachidonoyl glycerol (2-AG) and 2-arachidonyl glyceryl ether (2-AGE), were synthesized and their ability to activate the CB1 receptors was determined by the [35S]GTPgammaS binding assay using rat cerebellar membranes. The main goal of the study was to examine how the DMH end tail affects the activity properties of 2-AG (1) and its stable ether (2) and urea analogues (5). The importance of the chain length was also explored by synthesizing 2-AG and 2-AGE derivatives (3 and 4) possessing the chain length C21 instead of C22. Replacement of the pentyl end chain with the DMH resulted in distinct potency decrease as compared to the reference compounds. The modification did not have such a strong impact on the efficacy values. In fact, the efficacy of the derivatives of 2-AGE (2 and 4) was comparable or even improved. Introducing a more stable and hydrophilic urea bond led to a dramatic decrease in biological activity.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. Teija.Parkkari@uku.fi
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.forename: Outi M H
authors.initials: OM
authors.lastname: Salo
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
mesh_terms: D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D063388:Endocannabinoids; D004987:Ethers; D005989:Glycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D004987:Ethers; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C094503:glyceryl 2-arachidonate