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.

Research highlights
► The cannabilactone CB2 agonist AM1710 lacks off-target activity at other receptors.
► AM1710 crosses the blood brain barrier, albeit at low levels.
► Antinociceptive effects of AM1710 outlast that of the CB2 agonist (R,S)-AM1241.
► AM1710 produces thermal antinociception dominated by the CB2 receptor.
► AM1710 does not produce central side-effects in the tetrad.