A Guide to Targeting the Endocannabinoid System in Drug Design

Abstract

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

Positive Allosteric Modulation of CB1 and CB2 Cannabinoid Receptors Enhances the Neuroprotective Activity of a Dual CB1R/CB2R Orthosteric Agonist

“…Indeed, B2 concentrations exhibiting effective anti-inflammatory action and promoting the microglial switch to the neuroprotective phenotype, but unable to control the glutamate release, were proven effective on glutamate release in the presence of GAT229. As far as the CB1R is concerned, although the receptor seems to also be involved in maintaining the glutamate NMDAR activity within safe limits, thereby protecting neural cells from excitotoxicity; although the direct activation of the receptor seems responsible for effects of other long-time known drugs such as the analgesic paracetamol; and although targeting the CB1R is considered a proper direction against neurodegenerative diseases and neuroinflammation [ 52 ]—the possible psychoactive effects of the receptor activation via orthosteric ligands cannot be ignored.…”

Role of Cannabinoid Receptors in Psychological Disorder

“…Before discussing the ECS's functions, it is essential to understand its components. The ECS comprises cannabinoid receptors, endogenous ligands (binding molecules) for those receptors, and enzymes that synthesize and degrade the ligands (Stasiulewicz et al, 2020).…”

“…The neural mechanisms by which endocannabinoid signaling affects anxiety are not well understood, yet several mechanisms at the systems, synaptic, and molecular level can be posed based on available data. The majority of available data indicate that ECS has anxiolytic properties in both conditioned and unconditioned anxiety models and that these effects are more active during states of stress or high arousal (Stasiulewicz et al, 2020;Patel & Hillard, 2009). Endocannabinoid signaling's anxiolytic effects are mimicked by low doses of direct CB1 receptor agonists (Hill et al, 2018).…”

Cannabidiol in epilepsy: The indications and beyond

“…Cannabinoids bind to G-protein-coupled cell membrane cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors as well as G protein-coupled receptors (GPRs) 18, 55, and 119; transient receptor potential vanilloid type 1 channel (TRPV1), and peroxisome proliferator-activated receptor c. 9 The CB1 receptors are found throughout the central nervous system and concentrate in the cortex, basal ganglia, hippocampus, and cerebellum on axon terminals and preterminal axon segments. And the CB2 receptors are less abundant and are found on microglia, vascular tissues, immune cells, and a few neuron types.…”

“…10 Cannabinoid type 1 receptor activation causes decreased presynaptic glutamate release. 9 Endogenous cannabinoids (endocannabinoids) seem to decrease excitotoxicity by occupation of the CB1 receptors on glutamatergic neurons. Two prevalent endocannbinoids are anandamide and 2-arachidonoylglycerol.…”