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Imidazole-derived agonists for the neurotensin 1 receptor.

ABSTRACT: A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1?M against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented.

SUBMITTER: Hershberger PM

PROVIDER: S-EPMC3898338 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Imidazole-derived agonists for the neurotensin 1 receptor.

Hershberger Paul M PM Hedrick Michael P MP Peddibhotla Satyamaheshwar S Mangravita-Novo Arianna A Gosalia Palak P Li Yujie Y Gray Wilson W Vicchiarelli Michael M Smith Layton H LH Chung Thomas D Y TD Thomas James B JB Caron Marc G MG Pinkerton Anthony B AB Barak Lawrence S LS Roth Gregory P GP

Bioorganic & medicinal chemistry letters 20131121 1

A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1μM against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 an ...[more]

PMID: 24332089

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

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| S-EPMC4130903 | biostudies-literature

Histamine H3-receptor agonists and imidazole-based H3-receptor antagonists can be thermodynamically discriminated.

Project description:BACKGROUND AND PURPOSE: Studies suggest that measurement of thermodynamic parameters can allow discrimination of agonists and antagonists. Here we investigate whether agonists and antagonists can be thermodynamically discriminated at histamine H(3) receptors. EXPERIMENTAL APPROACH: The pK(L) of the antagonist radioligand, [(3)H]-clobenpropit, in guinea-pig cortex membranes was estimated at 4, 12, 21 and 30 degrees C in 20 mM HEPES-NaOH buffer (buffer A), or buffer A containing 300 mM CaCl(2), (buffer A(Ca)). pK(I)' values for ligands with varying intrinsic activity were determined in buffer A and A(Ca) at 4, 12, 21 and 30 degrees C. KEY RESULTS: In buffer A, the pK(L) of [(3)H]-clobenpropit increased with decreasing temperature while it did not change in buffer A(Ca). The Bmax was not affected by temperature or buffer and n (H) values were not different from unity. In buffer A, pK(I)' values for agonists remained unchanged or decreased with decreasing temperature, while antagonist pK(I) values increased with decreasing temperature; agonist binding was entropy-driven while antagonist binding was enthalpy and entropy-driven. In buffer A(Ca), temperature had no effect on antagonist and agonist pK(I) values; both agonist and antagonist binding were enthalpy and entropy-driven. CONCLUSIONS AND IMPLICATIONS: The binding of H(3)-receptor agonists and antagonists can be thermodynamically discriminated under conditions where agonist pK(I)' values are over-estimated (pK(I)' not = pK(app)). However, under conditions when agonist pK(I) approximately pK(app), the thermodynamics underlying the binding of agonists are not different to those of antagonists.

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Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

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

Project description:Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophrenia, addiction, or cancer. Neurotensin (NT) and Contulakin-G, a glycopeptide isolated from a predatory cone snail Conus geographus, share a sequence similarity at the C-terminus, which is critical for activation of neurotensin receptors. Both peptides are potent analgesics, although affinity and agonist potency of Contulakin-G toward neurotensin receptors are significantly lower, as compared to those for NT. In this work, we show that the weaker agonist properties of Contulakin-G result in inducing significantly less desensitization of neurotensin receptors and preserving their cell-surface density. Structure-activity relationship (SAR) studies suggested that both glycosylation and charged amino acid residues in Contulakin-G or NT played important roles in desensitizing neurotensin receptors. Computational modeling studies of human neurotensin receptor NTS1 and Contulakin-G confirmed the role of glycosylation in weakening interactions with the receptors. Based on available SAR data, we designed, synthesized, and characterized an analog of Contulakin-G in which the glycosylated amino acid residue, Gal-GalNAc-Thr10, was replaced by memantine-Glu10 residue. This analog exhibited comparable agonist potency and weaker desensitization properties as compared to that of Contulakin-G, while producing analgesia in the animal model of acute pain following systemic administration. We discuss our study in the context of feasibility and safety of developing NT therapeutic agents with improved penetration across the blood-brain barrier. Our work supports engineering peptide-based agonists with diverse abilities to desensitize G-protein coupled receptors and further emphasizes opportunities for conotoxins as novel pharmacological tools and drug candidates.

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Thermostabilization of the neurotensin receptor NTS1.

Project description:Structural studies on G-protein-coupled receptors have been hampered for many years by their instability in detergent solution and by the number of potential conformations that receptors can adopt. Recently, the structures of the beta(1) and beta(2) adrenergic receptors and the adenosine A(2a) receptor were determined in the antagonist-bound state, a receptor conformation that is thought to be more stable than the agonist-bound state. In contrast to these receptors, the neurotensin (NT) receptor NTS1 is much less stable in detergent solution. We have therefore used a systematic mutational approach coupled with activity assays to identify receptor mutants suitable for crystallization, both alone and in complex with the peptide agonist NT. The best receptor mutant NTS1-7m contained four point mutations. It showed increased stability compared to the wild-type receptor, in the absence of ligand, after solubilization with a variety of detergents. In addition, NTS1-7m bound to NT was more stable than unliganded NTS1-7m. Of the four thermostabilizing mutations, only one residue (A86L) is predicted to be in the lipid environment. In contrast, I260A appears to be buried within the transmembrane helix bundle, F342A may form a distant part of the putative ligand-binding site, whereas F358A is likely to be in a region that is important for receptor activation. NTS1-7m binds NT with a similar affinity for the wild-type receptor. However, agonist dissociation was slower, and NTS1-7m activated G-proteins poorly. The affinity of NTS1-7m for the antagonist SR48692 was also lower than that of the wild-type receptor. Thus, we have successfully stabilized NTS1 in an agonist-binding conformation that does not efficiently couple to G-proteins.

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Imaging Neurotensin Receptor in Prostate Cancer With <sup>64</sup>Cu-Labeled Neurotensin Analogs.

Project description:IntroductionNeurotensin receptor 1 (NTR-1) is expressed and activated in prostate cancer cells. In this study, we explore the NTR expression in normal mouse tissues and study the positron emission tomography (PET) imaging of NTR in prostate cancer models.Materials and methodsThree 64Cu chelators (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid [DOTA], 1,4,7-triazacyclononane-N,N',N?-triacetic acid [NOTA], or AmBaSar) were conjugated to an NT analog. Neurotensin receptor binding affinity was evaluated using cell binding assay. The imaging profile of radiolabeled probes was compared in well-established NTR+ HT-29 tumor model. Stability of the probes was tested. The selected agents were further evaluated in human prostate cancer PC3 xenografts.ResultsAll 3 NT conjugates retained the majority of NTR binding affinity. In HT-29 tumor, all agents demonstrated prominent tumor uptake. Although comparable stability was observed, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT demonstrated improved tumor to background contrast compared with 64Cu-DOTA-NT. Positron emission tomography/computed tomography imaging of the NTR expression in PC-3 xenografts showed high tumor uptake of the probes, correlating with the in vitro Western blot results. Blocking experiments further confirmed receptor specificity.ConclusionsOur results demonstrated that 64Cu-labeled neurotensin analogs are promising imaging agents for NTR-positive tumors. These agents may help us identify NTR-positive lesions and predict which patients and individual tumors are likely to respond to novel interventions targeting NTR-1.

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Structure of the agonist-bound neurotensin receptor.

Project description:Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8?Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

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Neurotensin-induced miR-133? expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin.

Project description:Neurotensin (NT) triggers signaling in human colonic epithelial cells by activating the G protein-coupled receptor, the neurotensin receptor 1 (NTR1). Activated NTR1 traffics from the plasma membrane to early endosomes, and then recycles. Although sustained NT/NTR1 signaling requires efficient NTR1 recycling, little is known about the regulation of NTR1 recycling. We recently showed that NT/NTR1 signaling increases expression of miR-133?. Herein, we studied the mechanism of NT-regulated miR-133? expression and examined the role of miR-133? in intracellular NTR1 trafficking in human NCM460 colonocytes. We found that NT-induced miR-133? upregulation involves the negative transcription regulator, zinc finger E-box binding homeobox 1. Silencing of miR-133? or overexpression of aftiphilin (AFTPH), a binding target of miR-133?, attenuated NTR1 trafficking to plasma membrane in human colonocytes, without affecting NTR1 internalization. We localized AFTPH to early endosomes and the trans-Golgi network (TGN) in unstimulated human colonic epithelial cells. AFTPH overexpression reduced NTR1 localization in early endosomes and increased expression of proteins related to endosomes and the TGN trafficking pathway. AFTPH overexpression and de-acidification of intracellular vesicles increased NTR1 expression. Our results suggest a novel mechanism of GPCR trafficking in human colonic epithelial cells by which a microRNA, miR-133? regulates NTR1 trafficking through its downstream target AFTPH.

| S-EPMC4763298 | biostudies-literature

Conformational Changes in Tyrosine 11 of Neurotensin Are Required to Activate the Neurotensin Receptor 1.

Project description:Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology and most peptides signal through G protein-coupled receptors (GPCRs). Disordered peptides bind GPCRs through complex modes for which there are few representative crystal structures. The disordered peptide neurotensin (NT) is a neuromodulator of classical neurotransmitters such as dopamine and glutamate, through activation of neurotensin receptor 1 (NTS1). While several experimental structures show how NT binds NTS1, details about the structural dynamics of NT during and after binding NTS1, or the role of peptide dynamics on receptor activation, remain obscure. Here saturation transfer difference (STD) NMR revealed that the binding mode of NT fragment NT10-13 is heterogeneous. Epitope maps of NT10-13 at NTS1 suggested that tyrosine 11 (Y11) samples other conformations to those observed in crystal structures of NT-bound NTS1. Molecular dynamics (MD) simulations confirmed that when NT is bound to NTS1, residue Y11 can exist in two χ1 rotameric states, gauche plus (g+) or gauche minus (g-). Since only the g+ Y11 state is observed in all the structures solved to date, we asked if the g- state is important for receptor activation. NT analogues with Y11 replaced with 7-OH-Tic were synthesized to restrain the dynamics of the side chain. P(OH-TIC)IL bound NTS1 with the same affinity as NT10-13 but did not activate NTS1, instead acted as an antagonist. This study highlights that flexibility of Y11 in NT may be required for NT activation of NTS1.

| S-EPMC7432660 | biostudies-literature

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