Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition

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.