Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter regulating numerous physiological functions, and its dysregulation is a crucial component of the pathological processes of schizophrenia, depression, migraines, and obesity. 5-HT interacts with 14 different receptors, of which 5-HT_1A-1FRs, 5-HT_2A-CRs, and 5-HT_4-7Rs are G protein-coupled receptors (GPCRs), while 5-HT₃R is a ligand-gated ion channel. Over the years, selective orthosteric ligands have been identified for almost all serotonin receptors, yielding several clinically relevant drugs. However, the high degree of homology between 5-HTRs and other GPCRs means that orthosteric ligands can have severe side effects. Thus, there has recently been increased interest in developing safer ligands of GPCRs, which bind to less conserved, more specific sites, distinct from that of the receptor’s natural ligand. The present review describes the identification of allosteric ligands of serotonin receptors, which are largely natural compounds (oleamide, cannabidiol, THC, and aporphine alkaloids), complemented by synthetic modulators developed in large part for the 5-HT_2C receptor. The latter are positive allosteric modulators sought after for their potential as drugs preferable over the orthosteric agonists as antiobesity agents for their potentially safer profile. When available, details on the interactions between the ligand and allosteric binding site will be provided. An outlook on future research in the field will also be provided.

This study presents the design, synthesis, and characterization of a novel series of structurally simple, selective, and functionally biased CB2 receptor (CB2R) agonists with potent anti-inflammatory and neuroprotective properties. These compounds were developed using a conformational restriction strategy to abolish CB1R binding, thereby enhancing CB2R selectivity. Pharmacological profiling identified ligands with distinct bias toward β-arrestin, MAPK, and G-protein signaling pathways. The series exhibits favorable drug-like properties, including high BBB permeability, low P-glycoprotein interaction, and microsomal stability. Representative compounds demonstrated neuroprotective activity in mouse primary neuronal assays and significantly reduced ROS and caspase levels in vitro, indicating mitigation of oxidative stress and apoptosis. In a neuron-like SH-SY5Y model expressing pathogenic mutations, they preserved neurite complexity in a CB2R-dependent manner. Collectively, these findings highlight the advantages of conformational restriction in transforming abused promiscuous, neurotoxic ligands into highly selective and efficacious agents for the treatment of neurodegenerative disorders, without CB1R-mediated psychoactive effects.

Over the past decade, oxidative stress and neuroinflammation have been increasingly recognized as part of the pathology of Alzheimer’s disease (AD). This observation has led to extensive efforts and attempts to apply antioxidant compounds as therapeutic agents for AD and other pathologies. However, most, if not all, of these attempts have failed in preclinical or clinical trials. A tentative explanation for this failure is radical scavengers’ intrinsic lack of specificity in either their mode or district of action. The lack of specificity has been thought by some to be a source of so-called “reductive stress”, another form of redox imbalance that might be just as toxic as oxidative stress. Thus, research interest is shifting from developing simple radical scavengers to designing and refining compounds targeting the overproduction of Reactive Oxygen Species (ROS) in specific pathological conditions. This can be achieved, for instance, by targeting the enzymes that are mainly responsible for their production, namely NADPH oxidases (NOX). In this review, we will discuss, from the point of view of medicinal chemistry, the main innovations in the development of NOX inhibitors and their potential employment for AD therapy. We will also discuss the experimental hurdles that slow down research in this field and possible solutions.

Chronic neuroinflammation and oxidative stress play an important role in the onset and progression of neurodegenerative disorders, including Alzheimer’s disease, which can ultimately lead to neuronal damage and loss. The mechanisms of sustained neuroinflammation and the coordinated chain of events that initiate, modulate, and then lead to the resolution of inflammation are increasingly being elucidated, offering alternative approaches for treating pathologies with underlying chronic neuroinflammation. Here, we propose a new multitarget approach to address chronic neuroinflammation and oxidative stress in neurodegenerative disorders by activating the formyl peptide receptor 2 (FPR2) combined with the potentiation of hydrogen sulfide (H₂S) release. FPR2 is a key player in the resolution of inflammation because it mediates the effects of several endogenous pro-resolving mediators. At the same time, H₂S is an endogenous gaseous transmitter with anti-inflammatory and pro-resolving properties, and it can protect against oxidative stress. Starting from potent FPR2 agonists identified in our laboratories, we prepared hybrid compounds by embedding an H₂S-donating moiety within the molecular scaffold of these FPR2 agonists. Following this approach, we identified several compounds that combined potent FPR2 agonism with the ability to release H₂S. The release of H₂S was assessed in buffer and intracellularly. Compounds 7b and 8b combined potent FPR2 agonist activity, selectivity over FPR1, and the ability to release H₂S. Compounds 7b and 8b were next studied in murine primary microglial cells stimulated with lipopolysaccharide (LPS), a widely accepted in vitro model of neuroinflammation. Both compounds were able to counterbalance LPS-induced cytotoxicity and the release of pro-inflammatory (IL-18, IL-6) and anti-inflammatory (IL-10) cytokines induced by LPS stimulation.