Scientists have been interested in neurotensin for the past 50 years as an alternative treatment option to conventional opioids, which would limit the harmful effects associated with opioids. Neurotensin is a compound that can reduce pain by acting on a receptor of the G protein coupled receptor (GPCR) family, the NTS1 or other types of receptors such as NTS2. NTS1 is found in the periphery (heart, intestine, other) and NTS2 is found in the central nervous system. A highly selective barrier separates the bloodstream and the central nervous system (including the brain). When neurotensin acts on the NTS1 receptor, it can also cause hypotension and hypothermia, due to the receptor distribution in the body. The goal is to achieve a targeted effect of neurotensin strictly on the NTS2 receptor in order to limit the adverse effects associated with the NTS1 receptor.<\/p>\n\n\n\n
The research team therefore conduced a literature review to assess the ligands (different forms of neurotensin) that act on the NTS2 receptor. In this review, researchers outline various modifications that can be made to neurotensin analogues\u2019 structure in order to increase neurotensin\u2019s affinity to the NTS2 receptor. Often, the greater the affinity, the smaller is the dose required to produce an analgesic effect. In addition, the desired compound should be able to cross the highly selective barrier between the bloodstream and the brain. To determine which modifications might have a beneficial effect on the desired molecule, scientists resort to structure-activity relationship (SAR) studies, which consider the relationships between molecules\u2019 structures and their biological activity.<\/p>\n\n\n\n
Macrocyclic compounds (as opposed to linear peptides) have a structure that allows them to have better pharmacological properties, activating the NTS2 receptor. There are also macrocycles that are not selective to the NTS2 receptor. It has been demonstrated in another article by Pr Sarret\u2019s research team that macrocycle 4 acts on NTS2 producing a high analgesic (pain relieving) effect with very few side effects related to NTS1. However, it is often not distributed to the brain after systemic injection administration and remains non-bioavailable. On the other hand, JMV20212 compound can produce a presumed pain-relieving effect in the brain after systemic injection. However, it\u2019s not sufficiently selective to the NTS2 receptor.<\/p>\n\n\n\n
The neurotensinergic system represents an interesting avenue to help scientists explore effective pharmacological solutions to tackle the opioid crisis and improve pain management. Analgesic treatments that selectively target NTS2 receptor are promising, however, many challenges remain to be solved in order to generate bioavailable molecules that are easily distributed to the brain.<\/p>\n\n\n\n