Therapeutic approaches targeting the neurotensin receptors

ABSTRACT

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
• sortilin
• radio-pharmaceuticals
• blood-brain-barrier
• psychostimulant abuse
• proneurotensin

Article highlights

• Since the discovery of neurotensin (NT) in 1973, multiple studies have appeared proposing the utility of this neuropeptide and its receptor modulators for therapeutics targets like pain, psychostimulant abuse, and cancer.

• While initial research was focused on NT-derived peptidic analogues, the last decade has witnessed several drug-discovery campaigns involving small-molecule non-peptidic ligands belonging to diverse scaffolds.

• Many agents based on the neurotensinergic system were in clinical trials although no clinical use of these agents has yet been approved.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an inventor of several patents and patent applications on NTR1 modulators. A reviewer on this manuscript has disclosed that they are also the PI on a grant from the National Institutes of Health (US) which is focused on the clinical development of an NTR1 modulator. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the NIAAA Intramural Research.