Pseudocannabinoids for mitigation of substance use disorder

Syncanica Bio, Sacramento CA

Investigators

Abstract

Project Summary Cannabidiol (CBD), the major component of Cannabis sativa, is best known for its anticonvulsant properties. It shows far more potent antiseizure activity and weaker narcotic action than its minor counterpart, ∆9-tetrahydrocannabinol (THC). Epidiolex, a herbal CBD preparation, was approved by the FDA in 2018 for the treatment of refractory seizures. However, CBD is a low potency drug, requiring up to 25 mg/kg dosing. In addition to this, chemical conversion of CBD to THC is trivial, requiring nothing more than a simple acid catalyst, and diversion of CBD to pure THC has the potential to spawn a culture similar to that of the "meth lab" phenomenon. Thus, with the goal to produce less controversial, non-controlled, abuse-proof and more potent drugs, Syncanica is developing fully synthetic analogs of 8,9-dihydrocannabidiol (H2CBD) as therapeutic agents. The startup was launched with a first-case use to provide a better drug for epilepsy. That venture is progressing, and the goal now is to broaden the range of indications. A new, high-potential therapeutic target is substance use disorder (SUD), a devastating public health crisis for which current treatments show limited effectiveness. Cannabis in general, and CBD specifically, has been widely investigated for its promise to manage addiction. Multiple literature sources indicate that CBD can induce analgesia and also attenuate opioid-induced reward while reducing withdrawal symptoms among individuals with opioid dependence. Interestingly, the opposite is true for THC, which enhances opioid reward self-administration, as well as inducing acute cognitive and motor impairment. Syncanica's task is now to develop and market a drug better than CBD in all respects. Already, literature evidence and our own work show that analoging can lead to significant changes in potency and action. Preliminary behavior studies also indicate that H2CBD has no sedative properties, unlike CBD, which is known to induce somnolence. Encouraged by these results and ample literature evidence pointing to CBD's potential in SUD therapy, we now propose to validate the pharmacological and pharmacokinetic properties of H2CBD and its analogs via the following Aims: Aim 1: Synthesize a series of H2CBD analogs. Efficient, scalable, synthetic routes to H2CBD and a set of 15 analogs will be employed to enable the follow-up pharmacological and pharmacokinetic studies in Aims 2 and 3. Aim 2: Evaluate H2CBD analogs in a zebrafish model of addiction and pain. The candidate compounds from Aim 1 will undergo preliminary testing in a larval zebrafish assay to confirm the absence of unwanted side effects including sedation and motor impairment. We will then utilize the zebrafish's robust nociceptive response to the photochemical irritant optovin to assess how H2CBD analogs attenuate pain related behaviors. Finally, efficacy in reducing drug-seeking behaviors will be quantified using an established adult zebrafish opioid self-administration assay. Aim 3: Conduct pharmacokinetic (PK) studies of H2CBD analogs in rodents. The PK parameters (exposure, distribution, and half-life) will be determined to ultimately determine dose ranges for a rodent study in Phase II and for the identification of the degradation pathways of H2CBD analogs by examining their metabolites, ultimately clearing the path for an IND application.