DRUG DESIGN, SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF NOVEL MULTIMODAL INDOLE-FUSED TRICYCLIC DERIVATIVES TARGETING CANNABINOID-MODULATED G PROTEIN-COUPLED RECEPTORS AND CHOLINESTERASES

Due to the multi-factorial nature of most neurological disorders, developing multi-target compounds is still considered among the effective approaches to developing neuroprotective drugs. Despite the scientific advances in the areas of neurochemistry, genetics, molecular and cell biology, there is still no effective treatment available that can delay the onset or slow the progression of neurodegenerative diseases, like Alzheimer’s disease (AD) and memory impairments. In the context of the challenging multitarget-directed-ligand (MTDL) design strategy of novel therapeutic agents for treating AD and related syndromes, progress has been made in the medicinal chemistry of drugs acting within and beyond the endocannabinoid system. Endogenous lipids, such as palmitoylethanolamide, that act simultaneously at GPCRs, ion channels, and PPARs can be taken as templates. In this Ph.D. thesis study, starting from the structures of small-molecules inhibiting well-established AD-related targets, such as cholinesterases (AChE and BChE) and N-methyl-D-aspartate (NMDA) receptor, the synthesis has been carried out of novel rationally designed tricyclic indole-fused derivatives which interestingly proved to act as modulators (antagonists and/or inverse agonists) of the cannabinoid-related GPCRs GPR18 and GPR55, in some cases endowed with additional BChE-selective inhibition. The desired outcome is the combination of the anticholinesterase activity with the modulation of these poorly studied receptors, for a synergistic effect against neuroinflammation and neurodegeneration. Structure−activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Chemical synthesis and analysis, radioligand binding and functional assays, enzymes’ inhibition kinetics and molecular modeling studies, in addition to allowing us to select candidates for in vivo pharmacological evaluation, provided us with useful medicinal chemistry information enabling the optimization of MTDLs against neurological disorders, potentially more effective than the currently available.