Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field.

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.