Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.
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.
Valenzano
Kenneth J
KJ
Department of Pharmacology, Purdue Pharma Discovery Research, Cranbury, NJ 08512, USA. ken.valenzano@pharma.com
Tafesse
Laykea
L
Lee
Gary
G
Harrison
James E
JE
Boulet
Jamie M
JM
Gottshall
Susan L
SL
Mark
Lilly
L
Pearson
Michelle S
MS
Miller
Wendy
W
Shan
Shen
S
Rabadi
Leyana
L
Rotshteyn
Yakov
Y
Chaffer
Suzanne M
SM
Turchin
Paul I
PI
Elsemore
David A
DA
Toth
Mathew
M
Koetzner
Lee
L
Whiteside
Garth T
GT
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
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