Abstract
Polypharmacology breaks up the classical paradigm of “one-drug, one target, one disease” electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.
Highlights
The endocannabinoid system (ECS) is a widespread neuromodulatory network that plays an important role in the regulation of many cognitive and physiological processes by modulating neuronal activity [1]
We focused our attention on the reported polypharmacological examples in which fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors are involved
The ECS appears to be of relevance as a therapeutic target in central nervous system (CNS) disorders, in neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), strokes, traumatic brain injury (TBI), pain, and epilepsy
Summary
The endocannabinoid system (ECS) is a widespread neuromodulatory network that plays an important role in the regulation of many cognitive and physiological processes by modulating neuronal activity [1]. The endocannabinoid signaling seems to be altered and hypofunctional in many neurological diseases; it could represent a critical component in the control of neuroinflammation and the pathogenesis of neurodegenerative disorders [2] These are complex diseases and are often due to the deregulation of multiple pathways, so treatment with single drugs is not effective enough. Hampering endocannabinoid degradation is an attractive strategy to obtain the indirect cannabinoid (CB) receptor activation Considering these assumptions, the present review aims to offer a glimpse of the current polypharmacological approaches involving FAAH and MAGL inhibitors, their dualism, and their polypharmacology involving other enzymes or systems with a focus on CNS disorders and especially neurodegenerative ones
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