The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1)

Abstract

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson’s disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca2+ mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 μM at NTSR1 with full agonist behaviour (Emax = 100%), showing a higher efficacy and ~ 90-fold potency improvement compared to parent compound 1 (EC50 = 178 μM; Emax = 17%).

Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism

“…This rotation may go hand in hand Cβ VII F331 with the rotation of the guanidinium head group of R328 6.55 toward the agonist's carboxylate, as captured in the structure of NTSR1-ELF (10). The rearrangement of the latter side chain may underlie the highly beneficial effect of a carboxylate group for ligand agonism (22), in addition to the anchoring function exerted through a salt bridge with R327 6.54 (Fig. 3, A to C).…”

“…Although the presence of an l-Leu moiety is highly beneficial for agonist potency and efficacy (21,22,48), its presence is not sufficient to guarantee receptor activation (neither full nor partial), and the question thus arises of how other functional groups in agonist ligands modulate receptor activation. The structures obtained in this study now allow us to broadly address this question.…”

Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators

“…17 In addition, a weakly active indole based partial agonist from Wyeth 18 and an optimized full agonist analogue from Scripps (SR-12062) have been reported. 19 We have reported on a series of β-arrestin biased quinazoline positive modulators of NTR1, exemplified by our probe compound ML314 (Figure 2). 20 While ML314 was moderately potent, displayed good brain penetration after IP dosing, and was active in vivo in a number of animal models of addiction, 21 it displayed low oral bioavailability (<5%).…”

“…Positive modulators include sub-μM compounds from RTI, which was derived from the SR compounds, and the related imidazole ML301 . In addition, a weakly active indole based partial agonist from Wyeth and an optimized full agonist analogue from Scripps (SR-12062) have been reported . We have reported on a series of β-arrestin biased quinazoline positive modulators of NTR1, exemplified by our probe compound ML314 (Figure ).…”

A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties

“…Branched NT analogs have anticancer ( Falciani et al, 2010 , 2013a , b ) and anti-apoptotic activities ( Devader et al, 2013 ). Recent advances in developing new agonists for NT receptors include NTS-1 selective small-molecules ( Peddibhotla et al, 2013 ; Di Fruscia et al, 2014 ; Hershberger et al, 2014 ) and NTS2-selective mimetics ( Einsiedel et al, 2011 ; Held et al, 2013 ). Pleiotropic nature of NT includes promoting progression of certain types of cancer ( Wu et al, 2013 ), providing new challenges and opportunities for preclinical and clinical development of NT-based analogs.…”