Receptor Specificity Engineering of TNF Superfamily Ligands

The tumor necrosis factor (TNF) ligand family has nine ligands that show promiscuity in binding multiple receptors. As different receptors transduce into diverse pathways, the study on the functional role of natural ligands is very complex. In this review, we discuss the TNF ligands engineering for receptor specificity and summarize the performance of the ligand variants in vivo and in vitro. Those variants have an increased binding affinity to specific receptors to enhance the cell signal conduction and have reduced side effects due to a lowered binding to untargeted receptors. Refining receptor specificity is a promising research strategy for improving the application of multi-receptor ligands. Further, the settled variants also provide experimental guidance for engineering receptor specificity on other proteins with multiple receptors.

Effects of imidazoline agents in a rat conditioned place preference model of addiction

Agmatine (AG), idazoxan (IDZ), and efaroxan (EFR) are imidazoline receptor ligands with beneficial effects in central nervous system disorders. The present study aimed to evaluate the interaction between AG, IDZ, and EFR with an opiate, tramadol (TR), in a conditioned place preference (CPP) paradigm. In the experiment, we used five groups with 8 adult male Wistar rats each. During the condition session, on days 2, 4, 6, and 8, the rats received the drugs (saline, or TR, or IDZ and TR, or EFR and TR, or AG and TR) and were placed in their least preferred compartment. On days 1, 3, 5, and 7, the rats received saline in the preferred compartment. In the preconditioning, the preferred compartment was determined. In the postconditioning, the preference for one of the compartments was reevaluated. TR increased the time spent in the non-preferred compartment. AG decreased time spent in the TR-paired compartment. EFR, more than IDZ, reduced the time spent in the TR-paired compartment, but without statistical significance. AG reversed the TR-induced CPP, while EFR and IDZ only decreased the time spent in the TR-paired compartment, without statistical significance.

TRYPTOPHAN: A KEY METABOLITE OF HOMEOSTASIS AND A REGULATOR OF BODY FUNCTIONS

Background. Tryptophan is an essential amino acid found mainly in protein foods and its availability is highly dependent on a diet. A significant part of tryptophan is metabolized in the gastrointestinal tract by the intestinal microbiota, producing a number of biologically active molecules, including aryl hydrocarbon receptor ligands, kynurenines, and serotonin (5-hydroxytryptamine). Objective. To analyze scientific studies confirming the key role of tryptophan microbial catabolites on the function of a macroorganism. Material and methods. The analysis of 47 English-language literature sources containing information on the effects of tryptophan metabolites on the mammalian organism was carried out. Results. It has been established that tryptophan metabolism plays a central role both in a normal macroorganism and in pathological conditions, it being directly or indirectly controlled by the intestinal microbiota. Conclusions. Thus, tryptophan metabolism is an important therapeutic target, underutilized in the treatment of a number of chronic neurological pathologies and immunocompetent conditions. An important factor is the use of nutraceuticals and probiotics by microorganisms that modulate the metabolism of tryptophan in the intestine and stimulate the synthesis of specific metabolites.

Overcoming Depression with 5-HT2A Receptor Ligands

Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT2A) receptor facilitated design and discovery of novel compounds with antidepressant action. Eligible papers highlighting the importance of 5-HT2A receptors in the pathomechanism of the disorder were identified in the content-screening performed on the popular databases (PubMed, Google Scholar). Articles were critically assessed based on their titles and abstracts. The most accurate papers were chosen to be read and presented in the manuscript. The review summarizes current knowledge on the applicability of 5-HT2A receptor signaling modulators in the treatment of depression. It provides an insight into the structural and physiological features of this receptor. Moreover, it presents an overview of recently conducted virtual screening campaigns aiming to identify novel, potent 5-HT2A receptor ligands and additional data on currently synthesized ligands acting through this protein.

Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by in vitro Cellular Studies and in vivo PET Imaging

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in the brain. Previously, we found that varenicline is trapped in intracellular acidic vesicles that contain α4β2-type nicotinic receptors (α4β2Rs). Nicotine is not trapped but concentrates there. Here, combining subcellular methods with in vivo PET imaging, we present evidence that the α4β2R PET ligand, 2-FA85380 (2-FA), is trapped within α4β2R-containing acidic vesicles, while the PET ligand, Nifene, is not trapped. Additional evidence, using a fluorescent-tagged α4β2R PET ligand, Nifrolidine, identified the trapping vesicles as Golgi satellites, an organelle regulated by nicotine in neurons where α4β2Rs are expressed and traffics and processes α4β2Rs in those neurons. Using PET imaging, 2-[18F]FA kinetics in high α4β2R-expressing regions were much slower than ligand unbinding rates consistent with 2-FA trapping in Golgi satellites extending ligand residence time and 2-[18F]FA imaging of the Golgi satellites. Chloroquine, which dissipates acidic organelle pH gradients, reduced 2-[18F]FA distribution in vivo consistent with ligand trapping. In contrast, [18F]Nifene kinetics were rapid, consistent with ligand residence time reflecting ligand unbinding rates, and [18F]Nifene imaging all α4β2R pools. Specific 2-[18F]FA and [18F]Nifene signals were eliminated in β2 subunit knockout mice or by acute nicotine injections demonstrating binding to high-affinity sites on β2-containing receptors. Altogether, we find that kinetic differences in α4β2R PET ligands are consistent with their distribution among different α4β2R pools in the brain, [18F]Nifene binding and imaging all ligand-binding α4β2Rs and 2-[18F]FA imaging α4β2Rs in Golgi satellites.