title: Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.
abstract: To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.
authors.affiliation: Department of Pharmacology, Purdue Pharma Discovery Research, Cranbury, NJ 08512, USA. ken.valenzano@pharma.com
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: Laykea
authors.initials: L
authors.lastname: Tafesse
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: James E
authors.initials: JE
authors.lastname: Harrison
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Boulet
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gottshall
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Pearson
authors.forename: Wendy
authors.initials: W
authors.lastname: Miller
authors.forename: Shen
authors.initials: S
authors.lastname: Shan
authors.forename: Leyana
authors.initials: L
authors.lastname: Rabadi
authors.forename: Yakov
authors.initials: Y
authors.lastname: Rotshteyn
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Chaffer
authors.forename: Paul I
authors.initials: PI
authors.lastname: Turchin
authors.forename: David A
authors.initials: DA
authors.lastname: Elsemore
authors.forename: Mathew
authors.initials: M
authors.lastname: Toth
authors.forename: Lee
authors.initials: L
authors.lastname: Koetzner
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
mesh_terms: D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001007:Anxiety / Q000378:metabolism*; D001259:Ataxia / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002375:Catalepsy / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D000588:Amines; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D003509:Cyclohexanecarboxylic Acids; D003511:Cyclohexanols; D018691:Excitatory Amino Acid Antagonists; D007166:Immunosuppressive Agents; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D043885:Receptor, Cannabinoid, CB2; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077206:Gabapentin; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; D007213:Indomethacin