Oxytocin and vasopressin signaling in health and disease.

Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.

Neuropeptide signalling systems - An underexplored target for venom drug discovery.

Neuropeptides are signalling molecules mainly secreted from neurons that act as neurotransmitters or peptide hormones to affect physiological processes and modulate behaviours. In humans, neuropeptides are implicated in numerous diseases and understanding their role in physiological processes and pathologies is important for therapeutic development. Teasing apart the (patho)physiology of neuropeptides remains difficult due to ligand and receptor promiscuity and the complexity of the signalling pathways. The current approach relies on a pharmacological toolbox of agonists and antagonists displaying high selectivity for independent receptor subtypes, with the caveat that only few selective ligands have been discovered or developed. Animal venoms represent an underexplored source for novel receptor subtype-selective ligands that could aid in dissecting human neuropeptide signalling systems. Multiple endogenous-like neuropeptides as well as peptides acting on neuropeptide receptors are present in venoms. In this review, we summarise current knowledge on neuropeptides and discuss venoms as a source for ligands targeting neuropeptide signalling systems.

Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development.

Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of diseaserelated pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity, substance use disorders and impulse control disorders while antagonists may add value for the treatment of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDAapproved anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators (PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs are discussed in this review.