New Approaches in the Design and Development of Cannabinoid Receptor Ligands: Multifunctional and Bivalent Compounds

Abstract

Since the identification of the endocannabinoid system, two G protein-coupled receptors (GPCRs) of this complex system were identified and characterized: cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). In addition to orthosteric and subsequently allosteric ligands, new strategies have been used to target CBRs. Bivalent ligands and multifunctional ligands acting at diverse biological targets have been designed, synthesized, and characterized for both CBRs. Due to their altered receptor binding and pharmacological profiles, they are interesting tools to explore CBR functions and their interactions with other physiological systems. Moreover, this approach may bear therapeutic advantages in the therapy of CBR-related disorders, especially multifactorial diseases. Promising prospects include anorectics with fewer side effects, analgesics with decreased tolerance, and therapeutics with multiple pharmacological activities for the treatment of cancer, inflammation, multiple sclerosis, Huntington's and Alzheimer's diseases.

Aminobenzimidazoles and Structural Isomers as Templates for Dual‐Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders

“…Multitarget‐directed ligands, hybrid molecules and dual‐acting compounds are of special importance for the potential therapy of neurodegenerative disorders . Over‐synergistic effects can result with the use of these compounds, and they show one coherent pharmacokinetic profile, in contrast to the administration of two single substances.…”

Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors

“…This way the pharmacokinetics and pharmacodynamics of the single drugs with substantially different absorption and partition properties will be the same, and a treatment method where the amount of the opioid component is subtherapeutic as compared to the administration without the cannabinoid can be applied. The strategy of combining GPCR ligands with various spacers to obtain multitargeting ligands is widely investigated with various success [76,77]. In our work JWH-018, a synthetic full agonist of CB receptors was covalently coupled with the semisynthetic opioid agonist oxycodone or with the enkephalin-related tetrapeptide agonist Tyr-D-Ala-Gly-Phe via spacers of different length and hydrophobicity.…”

Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation

“…At this date, the neuromolecular role of the endocannabinoid system in sleep-wake cycle regulation has provided important insights regarding the involvement of AEA, CB 1 cannabinoid receptor, AMT, as well as FAAH (Murillo-Rodríguez et al, 1998, 2001, 2003, 2007b, 2008a, 2011a, 2016; Herrera-Solis et al, 2010; Pava et al, 2014, 2016; Rueda-Orozco et al, 2010). However, the identification of new compounds targeting the endocananbinoid system will help validating the role of this system in sleep control highlighting the most pertinent drug with highest efficiency and lowest side effects in animal models (Lauria et al, 2015; Nimczick and Decker, 2015; Bertini et al, 2016; Aizpurua-Olaizola et al, 2017; Chicca et al, 2017). …”