Good news! Are we coming closer to effective painkillers without addiction?
"... "The custom-designed compound we created attaches to pain-reducing receptors in the body but, by design, it can't reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn't addictive because it doesn't act on the brain's reward center." ...
designed a cannabinoid molecule with a positive charge, preventing it from crossing the blood-brain barrier into the brain while allowing the molecule to engage CB1 receptors elsewhere in the body.
By modifying the molecule such that it only binds to pain-sensing nerve cells outside of the brain, the researchers achieved pain relief without mind-altering side effects. ..."
"... In this study, the modified compound offered prolonged pain relief – the animals showed no signs of developing tolerance despite twice-daily treatments with the compound over the course of nine days. This is a promising sign that the molecule could be used as a non addictive drug for relief of chronic pain, which requires continued treatment over time. ..."
From the abstract:
"The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations—an extended binding pocket that opens rarely and leads to the conserved signalling residue D2.50. We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment.
Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors."
Compound harnesses cannabis’ pain-relieving properties without side effects (original news release) "Mouse study points to an effective alternative to opioids"
A cryptic pocket in CB1 drives peripheral and functional selectivity (no public access)
The compound is illustrated here in cyan, nestled within a protein (green and purple) involved in sensing pain.
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