Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602

Abstract

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

“…Phytocannabinoids are soluble in lipids and nonpolar organic solvents [ 43 ]. Their lipophilicity is as follows: CBG > CBC > cannabitriol (CBT) > CBD > cannabielsoin (CBE) > THC > CBDV > CBN > cannabicycline (CBL) [ 50 ]. Their lipophilic nature means that they cross the blood–brain barrier and are readily distributed throughout the brain and nerve cell membranes.…”

“…It has little affinity for the CB 1 and CB 2 receptors [ 43 ]. CBL inhibits acetylcholinesterase (AChE) less than THC or CBN but more than CBD or CBG; it is less lipophilic than most cannabinoids [ 50 ]. The CBL structure is shown in Figure 3 .…”

Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action

“…Due to its antioxidant, anti-inflammatory, and neuroprotective properties, cannabidiol was proposed as a promising innovative strategy for Alzheimer’s disease [ 9 , 10 ]. Moreover, CBD reduces the hyperphosphorylation of tau protein [ 9 ], inhibits acetylcholinesterase activity [ 11 ], and deposition and expression of beta-amyloid [ 10 , 12 , 13 ]. These pharmacological points of action are involved in the complex pathogenesis of Alzheimer’s disease.…”

“…Acetylcholinesterase participates in the hydrolytic breakdown of acetylcholine in the CNS and is a target-site for cannabidiol and other bioactive chemical compounds of Cannabis sativa L. [ 22 , 23 , 24 , 25 ]. Recent studies have focused on explaining the basis of the interaction between CBD and acetylcholinesterase (AChE), a key enzyme in the pathogenesis of Alzheimer’s disease [ 11 , 26 ]. However, many years ago, it was discovered that cannabinoids influence the limbic system by the modulation of cholinergic neuron activity in the hippocampal area [ 27 ].…”

Cannabis sativa: Interdisciplinary Strategies and Avenues for Medical and Commercial Progression Outside of CBD and THC

“…In another in silico study, CBL, CBT, and CBE were assessed, and ranked in this order, to have acetylcholinesterase-inhibiting function. However, their inhibitory effects were less than those of THC, CBN, and CBDV [357]. Exactly how well in silico studies translate to clinical relevance, or even to in vitro and/or in vivo studies, restricts what conclusions can be accurately drawn.…”