title: Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.
abstract: delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Wiley
authors.forename: D R
authors.initials: DR
authors.lastname: Compton
authors.forename: P M
authors.initials: PM
authors.lastname: Gordon
authors.forename: C
authors.initials: C
authors.lastname: Siegel
authors.forename: M
authors.initials: M
authors.lastname: Singer
authors.forename: A
authors.initials: A
authors.lastname: Dutta
authors.forename: A H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: R L
authors.initials: RL
authors.lastname: Balster
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology; D002375:Catalepsy; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C106041:3-nor-pentyl-3-(1',1'-dimethylheptyl)-11-(N,N-bis(2-chloroethyl)amino)-delta(8)-tetrahydrocannabinol; C106042:5'-cyano-1',1'-dimethyl-delta(8)-tetrahydrocannabinol; D002186:Cannabinoids; D003511:Cyclohexanols; D009588:Nitrogen Mustard Compounds; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol