The Essential Medicinal Chemistry of Cannabidiol (CBD)

Abstract

This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.

Figure 1.

(A) The tetrahydro-diphenyl skeleton of CBD in the context of the base structures of three other main classes of cannabinoids (dibenzopyranes, benzopyranes, and acyclic prenyl-olivetols); as well as (B) five principal structural variations that occur in all cannabinoid classes. Different combinations of these four classes, with variations such as these presented as well as additional redox-driven metabolic modifications, explain why CBD and THC are just two molecules within the complex metabolome of cannabinoids.

Figure 2.

The biosynthetic pathway of cannabinoids is the result of the intersection of three metabolic pathways in Cannabis sp.

Figure 3.

The axial hydrogen, H-4”_ax, is involved not only in multiple J-coupling within the monoterpene moiety, but its ¹H NMR resonance is also affected by the close resonance behavior of its coupling partners. The resulting pronounced higher order effects of the ddddddq-type multiplet encode the spin parameters of half of the molecule in such a way that the H-4”ax resonance alone becomes diagnostic for the entire CBD molecule. See S1, Supporting Information, for the detailed results of the underlying ¹H iterative Full Spin Analysis (HiFSA).

Figure 4.

Structures of the active ingredients of FDA-approved drugs containing CBD or related compounds.

Figure 5.

Acid instability of cannabidiol as reported by Zynerba Pharmaceuticals.

Figure 6.

Selected bioactive synthetic analogs of cannabidiol

Figure 7. Interference profiling of CBD.

(A) CBD shows moderate activity at several receptors. K_i values reported from testing by PDSP. Full data in Supporting Information. (B) CBD shows concentration-dependent, detergent-sensitive inhibition of AmpC in a colloidal aggregation counter screen. TIPT, positive aggregation control; 2-BTBA, positive non-aggregator control. Data are mean SD of four intra-run technical replicates. (C) CBD shows detergent-sensitive inhibition of MDH in an orthogonal aggregation counter screen. Compounds were tested at 33 or 100 μM final concentrations in either the presence (blue) or absence (magenta) of buffer containing freshly-added 0.01% Triton X-100 (v/v). Data are mean SD of at least three intra-run technical replicates. (D) CBD forms detectible colloidal aggregates at approximately 12.5 μM by DLS. (E) CBD does not produce detectable H₂O₂ in a HRP-PR redox-cycling counter screen. Compounds assayed at 250 μM final concentrations 1 mM DTT, enzyme. H₂O₂, positive control; NSC-663284 and 4-amino-1-naphthol, positive control compounds. Data are mean SD of at least three intra-run technical replicates.

Figure 8.

Major metabolites of cannabidiol.