title: The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model.
abstract: The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-Delta8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects. Conversely, 2-iodo substitution on the phenolic ring leads to a 2-fold reduction in affinity while iodo-substitution in the C1'-position of the side chain lowers the compound's affinity for CB1 by more than 8-fold. The pharmacophoric requirements resulting from halogen-substitution are explored using computer modeling methods.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Drug Discovery, University of Connecticut, 372 Fairfield Road, Storrs, CT 06269, USA.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grzybowska
authors.forename: Demetris P
authors.initials: DP
authors.lastname: Papahatjis
authors.forename: Avgui
authors.initials: A
authors.lastname: Charalambous
authors.forename: Ali R
authors.initials: AR
authors.lastname: Banijamali
authors.forename: Ravi
authors.initials: R
authors.lastname: Chari
authors.forename: Pusheng
authors.initials: P
authors.lastname: Fan
authors.forename: Therapia
authors.initials: T
authors.lastname: Kourouli
authors.forename: Sonyuan
authors.initials: S
authors.lastname: Lin
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Nitowski
authors.forename: Gilbert
authors.initials: G
authors.lastname: Marciniak
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Li
authors.forename: Chia-Lin J
authors.initials: CL
authors.lastname: Wang
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006219:Halogens / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*
chemical_list: D006219:Halogens; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; C035731:delta-8-tetrahydrocannabinol; D013759:Dronabinol