Interactions of Cannabinoids With Biochemical Substrates

Abstract

Recent decades have seen much progress in the identification and characterization of cannabinoid receptors and the elucidation of the mechanisms by which derivatives of the Cannabis sativa plant bind to receptors and produce their physiological and psychological effects. The information generated in this process has enabled better understanding of the fundamental physiological and psychological processes controlled by the central and peripheral nervous systems and has fostered the development of natural and synthetic cannabinoids as therapeutic agents. A negative aspect of this decades-long effort is the proliferation of clandestinely synthesized analogs as recreational street drugs with dangerous effects. Currently, the interactions of cannabinoids with their biochemical substrates are extensively but inadequately understood, and the clinical application of derived and synthetic receptor ligands remains quite limited. The wide anatomical distribution and functional complexity of the cannabinoid system continue to indicate potential for both therapeutic and side effects, which offers challenges and opportunities for medicinal chemists involved in drug discovery and development.

Keywords: Cannabinoids; cannabinoid ligands; cannabinoid receptor subtypes; endocannabinoids; synthetic cannabinoids; Δ9-THC.

Figure 1

Δ⁹-THC, the principal psychoactive constituent in Cannabis sativa.

Figure 2

Four potent synthetic cannabinoids.

Figure 3

Radioligand autoradiograph of specific binding of [³H] CP-55,940 to a sagittal section of rat brain, showing high CB₁ receptor densities in the hippocampus, basal ganglia, and cerebellum.

Figure 4

Cannabinoid receptor signaling and trafficking. Modified and reproduced with permission from Al-Hasani and Bruchas.

Figure 5

The CB₁- and the CB₂-selective inverse agonists SR141716A (left) and SR144528 (right).

Figure 6

CB₁ allosteric modulators. Org 27569 (left) and PSNCBAM-1 (right) display positive binding cooperativity with the orthosteric agonist CP-55,940 for CB₁ receptor binding as would positive allosteric modulators, but reduce the efficacy of orthosteric agonists in several in vitro functional assays.

Figure 7

The endocannabinoids arachidonoylethanolamine (anandamide, left) and 2-arachidonoylglycerol (2-AG, right).

Figure 8

Neuronal endocannabinoid system. Reproduced with permission from Lu and Mackie.