Introduction: Neurotensin is a gut-brain peptide hormone, a 13 amino acid neuropeptide found in the central nervous system and in the GI tract. The neurotensinergic system is implicated in various physiological and pathological processes related to neuropsychiatric and metabolic machineries, cancer growth, food, and drug intake. NT mediates its functions through its two G protein-coupled receptors: neurotensin receptor 1 (NTS1/NTSR1) and neurotensin receptor 2 (NTS2/NTSR2). Over the past decade, the role of NTS3/NTSR3/sortilin has also gained importance in human pathologies. Several approaches have appeared dealing with the discovery of compounds able to modulate the functions of this neuropeptide through its receptors for therapeutic gain.Areas covered: The article provides an overview of over four decades of research and details the drug discovery approaches and patented strategies targeting NTSR in the past decade.Expert opinion: Neurotensin is an important neurotransmitter that enables crosstalk with various neurotransmitter and neuroendocrine systems. While significant efforts have been made that have led to selective agonists and antagonists with promising in vitro and in vivo activities, the therapeutic potential of compounds targeting the neurotensinergic system is still to be fully harnessed for successful clinical translation of compounds for the treatment of several pathologies.
Keywords: Neurotensin; blood-brain-barrier; proneurotensin; psychostimulant abuse; radio-pharmaceuticals; sortilin.