Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects

Cannabinoid CB₂ agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB₂ agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB₁ (SR141716) and CB₂ (SR144528) antagonists. AM1710 (0.1-10 mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5 mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB₂ agonist (R,S)-AM1241 (1 mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1 mg/kg i.p.) dose of AM1710 was blocked selectively by the CB₂ antagonist SR144528 (6 mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5 mg/kg i.p.) was blocked by either SR144528 (6 mg/kg i.p.) or SR141716 (6 mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB₂-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB₁-mediated antinociceptive effects of this compound may be attributable to peripheral CB₁ activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.