CT-3 (
ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported
analgesic efficacy in
neuropathic pain states in man. Here we show that CT-3 binds to human
cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional
GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory
pain in the rat,
oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of
mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist
SR141716A but not the CB2-antagonist
SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related
catalepsy, deficits in locomotor performance,
hypothermia, and acute
analgesia. Comparison of 50% maximal effects in the tetrad and
chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following
oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a
cannabinoid receptor agonist and is efficacious in animal models of
chronic pain by activation of the
CB1 receptor. Whilst it shows significant
cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other
cannabinoid compounds, which may reflect a relatively reduced CNS penetration.