Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Aron Lichtman
Second Advisor
Dana Selley
Third Advisor
Matthew Halquist
Abstract
Cannabinoid type-1 (CB1) receptor allosteric modulators represent an alternative strategy to target the CB1 receptor. These compounds bind to a separate, distinct site from the orthosteric site on the CB1 receptor, known as an allosteric site. When bound, these compounds lead to conformational changes in the protein structure of the G-protein coupled receptor (GPCR), which results in changes in the affinity and/or efficacy of the orthosteric ligands that bind to CB1. The changes made by these compounds that enhance or decrease affinity and efficacy are known as positive (PAM) or negative (NAM) allosteric modulators, respectively. With this characterization, they offer a possible therapeutic potential without the unwanted side effects associated with cannabis or orthosteric CB1 agonists. Unwanted side effects of cannabis include cognitive memory impairment and intoxication, as well as associations with psychiatric disorders such as anxiety, schizophrenia, depression, and use disorder.
The work presented in this thesis focused on CB1 positive allosteric modulators (PAMs). The CB1 PAM, ZCZ011, has been shown to be efficacious in reducing allodynia in various models of pain, as well as attenuating THC withdrawal signs, NSAID-induced gastric inflammation, and naloxone-precipitated diarrhea and weight loss in oxycodone-dependent mice. A structurally related CB1 PAM, GAT211, has been shown to be efficacious in suppressing allodynia by itself and synergizing with catabolic endocannabinoid enzyme inhibitors in various models of pain with tolerance or dependence, as well as enhancing antinociceptive effects of morphine while attenuating tolerance to the antinociceptive effects of morphine. Both of these CB1 PAMs also produced no cannabimimetic effects, such as decreased locomotor activity, catalepsy, antinociception, and hypothermia. However, the therapeutic potential of these CB1 PAMs may require the chronic usage of the drug in order to manage symptoms associated with the chronic conditions or disease. Therefore, it is important to assess the dependence liability of these CB1 PAMs.
In this study, we assess the cannabimimetic effects and dependence liability of novel CB1 positive allosteric modulators, PTDP-15 and PTDP-131, which are structurally related to the well characterized CB1 PAM ZCZ011 in the tetrad assay and adaptation of existing THC withdrawal paradigms. The tetrad assay, consisting of decreased locomotor activity, catalepsy, antinociception, and hypothermia, is very sensitive to CB1 receptor orthosteric agonists. None of the CB1 PAMs assessed produced cannabimimetic tetrad effects, which supports previous studies showing no cannabimimetic effects associated with CB1 PAMs. The withdrawal paradigm consisted of administering the CB1 PAM twice a day for 5.5 days and then challenging with the CB1 receptor antagonist rimonabant after the last CB1 PAM administration to precipitate withdrawal. Surprisingly, rimonabant precipitated a moderate magnitude of somatic withdrawal signs (e.g., paw flutters and head shakes) following repeated administration of each PAM. While there was some dependence liability, this magnitude was most similar to the magnitude elicited by repeated administration of low-dose THC (10 mg/kg) followed by rimonabant (10 mg/kg) challenge. Therefore, even at high doses of CB1 PAM, the dependence liability is comparable to a low dose of THC. Our findings demonstrate the successful use of an adapted THC withdrawal paradigm in assessing dependence in CB1 PAMs. Ultimately, these studies will provide insight into whether CB1 PAMs have promise as a pharmacological strategy without undesirable effects such as cannabimimetic effects and dependence liability.
Rights
© Peter Long Hoang
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
6-26-2024