LAS VEGAS – CNTX-6016, a highly-selective cannabinoid receptor type 2 (CB2) agonist, was found to provide adequate analgesia in preclinical models of neuropathic pain, according to study results presented at PAINWeek 2019 held September 3-7 in Las Vegas, Nevada.
The researchers evaluated CNTX-6016 potency using cyclic adenosine monophosphate (cAMP) assays, in which CNTX-6016 binding to human, rat, or dog CB2 receptors expressed in Chinese hamster ovarian cells was measured. The molecular selectivity of 10 mM CNTX-6016 was tested using radioligand binding assays with a standard panel of 67 enzymes, channels, and receptors.
CNTX-6016 was found to be a potent agonist to CB2 receptors, with EC50 of 13, 9, and 20 nM for receptors of human, rat, and dog origin, respectively. CNTX-6016 was not found to bind to any of the other 67 targets examined.
The efficacy of CNTX-6016 was examined using a male Wistar rat model of neuropathic pain obtained with partial nerve ligation of the sciatic nerve. Mechanical hyperalgesia was assessed 2-weeks post-ligation by measuring the paw withdrawal threshold response to increasing mechanical pressure. One hour post-administration, CNTX-6016 was found to provide dose-dependent analgesia at 0.1 and 0.3 mg/kg doses, and at 1, 3, and 10 mg/kg, with maximal effect at 1 mg/kg. The robust effect of CNTX-6016 observed when the drug was administered on day 1 at 1, 3, or 10 mg/kg was maintained with repeated twice-daily dosing at 10 mg/kg for 5 days. No evidence of tachyphylaxis was found.
A streptozotocin (STZ) neuropathic pain rat model was used to evaluate the antinociceptive effect of CNTX-601. Pain-like behavior was assessed using the Randall-Selitto test as paw withdrawal threshold, and central nervous system adverse events were evaluated using a rat locomotor activity assay.
In this STZ model, CNTX-6016 was found to have maximum efficacy compared with 30 mg/kg duloxetine at 3 mg/kg. CNTX-6016 was not found to have any dose-limiting central nervous system adverse events, while duloxetine significantly reduced rat locomotor activity.
Allometric scaling and in vitro-in vivo correlation were used to estimate human pharmacokinetic parameters and based on in vivo pharmacokinetic data from animals and in vitro data from human and animal hepatocytes. The thus-estimated effective dose for humans would be 120 mg daily.
“For the treatment of neuropathic pain conditions, CNTX-6016 has the potential to provide therapeutic efficacy with a favorable safety profile compared with current standards of care,” noted the researchers.
Stevens RM, Nicholson JR, Sauer A, et al. Evaluation of the selective oral CB2 agonist CNTX-6016 for the treatment of neuropathic pain: pharmacokinetic, efficacy, and safety findings from preclinical studies. Presented at: PAINWeek 2019, September 3-7, 2019; Las Vegas, Nevada. Poster 103.