In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models.
OBJECTIVE
Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are mu-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist.


METHODS
A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and mu-opioid receptor antagonists.


RESULTS
A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or mu-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity.


CONCLUSIONS
These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain.
Yao
B B
BB
Neurological Diseases Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Hsieh
G C
GC
Frost
J M
JM
Fan
Y
Y
Garrison
T R
TR
Daza
A V
AV
Grayson
G K
GK
Zhu
C Z
CZ
Pai
M
M
Chandran
P
P
Salyers
A K
AK
Wensink
E J
EJ
Honore
P
P
Sullivan
J P
JP
Dart
M J
MJ
Meyer
M D
MD
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D003251:Constriction, Pathologic / Q000150:complications; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007596:Joints / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012585:Sciatica / Q000188:drug therapy / Q000209:etiology
C527637:(1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone; D018712:Analgesics, Non-Narcotic; D003511:Cyclohexanols; D003521:Cyclopropanes; D007166:Immunosuppressive Agents; D009025:Morpholines; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D017868:Cyclic AMP-Dependent Protein Kinases