Chapter One – Chemical diversity, receptor binding affinity, and pharmacology of phytocannabinoids: Insights into neuronal mechanisms

Comparative studies of phytocannabinoids offer valuable insights into the therapeutic potential of cannabis. While Cannabis sativa can produce over 100 distinct phytocannabinoids, most are present only in trace amounts. This review examines the structural, biochemical, and pharmacological characteristics of five representative phytocannabinoids: cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (Δ⁹-THC), and cannabinol (CBN). We describe their biosynthetic pathways, abiotic transformations, and precursor roles in generating molecular diversity. Chemovar profiles are discussed based on seed bank data and chromatographic analyses of Brazilian-grown cultivars. Our findings suggest that high-CBD chemovars have recently emerged, possibly due to genetic drift from intensive hybridization. To evaluate the clinical relevance of these compounds, we conducted a systematic review and meta-analysis of binding affinities (Ki) for CB1, CB2, and other neuronal receptors. Δ⁹-THC and CBN showed high affinities for CB1 and CB2, while CBG, CBC, and CBD exhibited 10–100 times lower affinities. Statistical analysis confirmed significantly stronger CB1 and CB2 binding for Δ⁹-THC compared to CBD. These results support the hypothesis that non-psychotropic phytocannabinoids primarily act through non-canonical targets such as GPR55 (G Protein-Coupled Receptor 55), TRPV1 (Transient Receptor Potential Vanilloid 1), and TRPM8 (Transient Receptor Potential Melastatin 8), though affinity data for these receptors remain limited. Finally, we discuss preclinical pharmacological evidence highlighting how subtle structural differences yield distinct physiological effects. Our findings emphasize the need for expanded research into underexplored phytocannabinoids with unique therapeutic potential.