Our medicinal chemistry team are synthesising innovative libraries of cannabinoid molecules to discover and develop new clinical candidates with improved therapeutic properties.
Our work is focused on understanding the relationship between the molecular structure and pharmacological activity of cannabinoids. We use modern organic chemistry techniques to improve the potency, absorption, and metabolism of cannabinoids.
The ultimate aim of this work is to develop the highest quality cannabinoid medicines for clinical evaluation in epilepsy, cancer, and pain.
The molecular libraries developed by the medicinal chemistry team represent the crucial first steps in the cannabinoid drug development process and provide materials to virtually all elements of the Lambert Initiative team.
The cannabis plant produces more than 100 unique molecules but only two cannabinoids have been approved for clinical use; Marinol® for chemotherapy-induced nausea and vomiting, and Epidiolex® for Dravet syndrome. Despite the clinical utility of plant cannabinoids, the historical prohibition of cannabis has hindered research into the therapeutic potential of this diverse natural product class.
We have identified several phytocannabinoids functioning as non-selective GPR55 antagonists with efficacy in mouse models of epilepsy. This project will involve the physicochemical optimisation of these cannabinoid GPR55 antagonist leads for improved target selectivity, in vivo potency, and pharmacokinetic profile.
Cannabinoid receptors are expressed abundantly throughout the brain, but also in the periphery. The clinically-approved cannabinoid antagonist rimonabant was withdrawn from the market owing to adverse effects associated with its central nervous system penetration (CNS), while brain-permeable cannabinoid agonists like tetrahydrocannabinol produce intoxication.
By rational modification of lipophilicity, polar surface area, and number of hydrogen bond contributors, we have developed several cannabinoid agonists and antagonists with limited ability to cross the blood-brain barrier. Peripherally-restricted cannabinoids have analgesic activity in rodents (agonists) and utility in cardiovascular and metabolic diseases (antagonists). We are developing each of these classes as new cannabinoid therapeutics with reduced adverse effect profiles.
Research Team: Dr Samuel Banister, Dr Jia Lin Luo, Dr Adam Ametovski, Dr Lewis Martin, Dr Michael Udoh, Dr Elizabeth Cairns, Dr Richard Kevin, Professor Iain McGregor, Dr Thomas Wei and Professor Joseph Wu
The pharmacological treatment or management for many conditions can be achieved through various drug targets. Drugs that can interact with more than one target for the same condition have the potential to elicit greater therapeutic activity for that condition. This is especially advantageous for treatment-resistant conditions, such as pain and epilepsy.
We are designing molecules that can both activate cannabinoid type 1 receptors as well as inhibiting T-type calcium channels. Cannabinoids with this dual mechanism-of-action show enormous promise for the treatment of Dravet Syndrome and other forms of epilepsy. We are designing, synthesizing and optimizing these potential candidates that will then be validated using cellular screening before being evaluated in animal models of disease.
Many cannabinoids require specialized formulation due to poor chemical stability and complex absorption, distribution, and metabolism profiles. We are working to modify specific regions of cannabinoid molecules that we predict may address such issues. Our researchers are undertaking extensive investigations of the chemical modification of key plant cannabinoids with a focus on the so-called “tail region”, isoprene unit, and phenolic groups, in order to improve potency and metabolic stability.
We have analytically developed, synthesized and characterized a library of dozens of phytocannabinoid analogues based on the central scaffolds of tetrahydrocannabinol (THC) cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), cannabielsoin (CBE), and cannabicyclol (CBL).