Date of Award
Since the discovery of Δ9-THC, the pharmaceutical industry has continuously developed synthetic analogs intending to develop compounds that exhibit the bioactivity of natural cannabinoids but are devoid of its psychoactivity. Synthetic cannabinoids often exhibit potencies significantly greater than Δ9-THC, as do their metabolites. Phase I metabolism of synthetic cannabinoids bearing an indazole core predominantly proceeds through oxidative transformations to produce mono-hydroxylated variants of the parent compound. Recent studies have primarily focused on N-1/C-3 hydroxylated pentyl side chains and carboxamide linked groups. These compounds often retain affinity and potency for the CB1 receptor and are thought to contribute to the serious, sometimes fatal, toxic profiles associated with synthetic cannabinoids. Full pharmacokinetic profiles must be obtained for all major metabolites, including the relatively unexplored indazole core hydroxylations, to gain a complete understanding of the pharmacological effects of the parent compounds.
Methods to introduce hydroxylated N-1/C-3 moieties directly onto the indazole scaffold are well described in the literature; however, methods to directly introduce a hydroxyl moiety directly on the indazole core are nonexistent. Thus, the goal of this work was to develop a synthetic strategy to obtain synthetic cannabinoids with a hydroxylated indazole core directly from readily available and inexpensive 1H-indazole-carboxylic acid. A novel synthesis process comprised of simple, functional group transformation from readily available material was developed to obtain these enzyme-derived hydroxylated compounds. The process utilizes 1H-indazole-3-carboxylic acid as the starting material to obtain twelve synthetically novel cannabinoids with various N-1 side chains and C-3 linked groups in a seven-step process with overall yields between 10 and 19%. The synthesis described is functional group tolerant, does not require specialized equipment or extreme conditions, yields are reproducible, and could be used to produce a variety of compounds for future studies. These novel metabolites will ultimately be evaluated for their biological activity, and their pharmacological analysis may provide new insights into the biological effects of synthetic cannabinoids on the endocannabinoid system.
Pianovich, Nichole Ann, "Design and Synthesis of Novel Synthetic Cannabinoid 5-Hydroxy-1H-Indazole-3-Carboxamide Metabolites" (2022). University of New Orleans Theses and Dissertations. 2981.
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