scholarly journals Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Julian Budzinski ◽  
Simone Maschauer ◽  
Hiroyuki Kobayashi ◽  
Pierre Couvineau ◽  
Hannah Vogt ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Interaction ◽  
Endosomal Trafficking ◽  
Receptor Ligands ◽  
Bivalent Ligands ◽  
Neurotensin Receptor ◽  
Neuropsychiatric Diseases ◽  
Dopamine D3 ◽  
Neurotensin Receptor 1 ◽  
G Protein Coupled

AbstractBivalent ligands are composed of two pharmacophores connected by a spacer of variable size. These ligands are able to simultaneously recognize two binding sites, for example in a G protein-coupled receptor heterodimer, resulting in enhanced binding affinity. Taking advantage of previously described heterobivalent dopamine-neurotensin receptor ligands, we demonstrate specific interactions between dopamine D3 (D3R) and neurotensin receptor 1 (NTSR1), two receptors with expression in overlapping brain areas that are associated with neuropsychiatric diseases and addiction. Bivalent ligand binding to D3R-NTSR1 dimers results in picomolar binding affinity and high selectivity compared to the binding to monomeric receptors. Specificity of the ligands for the D3R-NTSR1 receptor pair over D2R-NTSR1 dimers can be achieved by a careful choice of the linker length. Bivalent ligands enhance and stabilize the receptor-receptor interaction leading to NTSR1-controlled internalization of D3R into endosomes via recruitment of β-arrestin, highlighting a potential mechanism for dimer-specific receptor trafficking and signalling.

scholarly journals Synthesis of adenosine analogues with indole moiety as human adenosine A 3 receptor ligands

2018 ◽  
Vol 5 (2) ◽  
pp. 171596 ◽  
Author(s):  
Yan Xia ◽  
Xiliang Zheng ◽  
Erkang Wang ◽  
Dongfeng Li ◽  
Ruibin Hou ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Interaction ◽  
Receptor Ligands ◽  
Structural Determinants ◽  
Endogenous Modulator ◽  
Anti Cancer ◽  
Adenosine Derivatives ◽  
G Protein Coupled ◽  
Modelling Approach

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A 1 , A 2A , A 2B and A 3 , which belong to the G-protein-coupled receptor superfamily. The human A 3 AR (hA 3 AR) subtype is implicated in several cytoprotective functions. Therefore, hA 3 AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hA 3 AR ligands. According to the biological assay, we found that 2-substituents 11 were critical structural determinants for A 3 AR ligands ( K i  = 111 nM). The observed structure–affinity relationships of this class of ligands were also exhaustively rationalized using the molecular modelling approach. This allows the investigation on the binding mode of the potential compound in the ligand-binding pocket of the human A 3 receptor. The results demonstrated that 11 can interact with the ASN250, GLN167, PHE168 and VAL178 through hydrogen bonding, which are shown to be important for ligand–receptor interaction.

Human and mouse trace amine-associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands

2009 ◽  
Vol 424 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Liaoyuan A. Hu ◽  
Tian Zhou ◽  
Jinwoo Ahn ◽  
Shuli Wang ◽  
Julia Zhou ◽  
...  
Keyword(s):  
Species Difference ◽  
Receptor Ligands ◽  
Imidazoline Receptor ◽  
Camp Assay ◽  
Neuropsychiatric Diseases ◽  
Trace Amine ◽  
Pharmacologically Active ◽  
G Protein Coupled ◽  
Human And Mouse

TAARs (trace amine-associated receptors) are G-protein-coupled receptors that respond to low abundance, endogenous amines such as tyramine and tryptamine, and represent potential targets for neuropsychiatric diseases. However, some members of this receptor subfamily either have no ligand identified or remain difficult to express and characterize using recombinant systems. In the present paper we report the successful expression of human and mouse TAAR1, and the characterization of their responses to various natural and synthetic agonists. In HEK (human embryonic kidney)-293/CRE-bla cells, mouse TAAR1 showed a robust response to trace amines as measured using either a cAMP assay or a β-lactamase reporter assay, whereas human TAAR1 showed a weaker, but still measurable, response. When certain fragments of human TAAR1 were replaced with the corresponding regions of mouse TAAR1, the chimaeric receptor showed a much stronger response in cAMP production. Examination of a series of agonists on these receptors revealed that the human and the chimaeric receptor are almost identical in pharmacology, but distinct from the mouse receptor. We also screened small libraries of pharmacologically active agents on TAAR1 and identified a series of synthetic agonists, some of which are also ligands of the enigmatic imidazoline receptor. The findings of the present study not only shed light on the pharmacological species difference of TAAR1, but also raise new possibilities about the mechanism of some of the imidazoline-related agents.

scholarly journals Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

2009 ◽  
Vol 19 (6) ◽  
pp. 1773-1778 ◽  
Author(s):  
Raquel Ortega ◽  
Enrique Raviña ◽  
Christian F. Masaguer ◽  
Filipe Areias ◽  
José Brea ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Dopamine D3 Receptor ◽  
D3 Receptor ◽  
Receptor Ligands ◽  
Dopamine D3

scholarly journals Constitutive Dimerization of the G-Protein Coupled Receptor, Neurotensin Receptor 1, Reconstituted into Phospholipid Bilayers

2009 ◽  
Vol 96 (3) ◽  
pp. 964-973 ◽  
Author(s):  
Peter J. Harding ◽  
Helen Attrill ◽  
Jonas Boehringer ◽  
Simon Ross ◽  
George H. Wadhams ◽  
...  
Keyword(s):  
G Protein ◽  
Phospholipid Bilayers ◽  
G Protein Coupled Receptor ◽  
Neurotensin Receptor ◽  
Neurotensin Receptor 1 ◽  
G Protein Coupled

Synthesis and binding affinity of new 1,4-disubstituted triazoles as potential dopamine D3 receptor ligands

2013 ◽  
Vol 23 (20) ◽  
pp. 5586-5591 ◽  
Author(s):  
Ignacio Insua ◽  
Mario Alvarado ◽  
Christian F. Masaguer ◽  
Alba Iglesias ◽  
José Brea ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Dopamine D3 Receptor ◽  
D3 Receptor ◽  
Receptor Ligands ◽  
Dopamine D3

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

2021 ◽  
Vol 7 (5) ◽  
pp. eabe5504
Author(s):  
Mattia Deluigi ◽  
Alexander Klipp ◽  
Christoph Klenk ◽  
Lisa Merklinger ◽  
Stefanie A. Eberle ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Binding Mode ◽  
Receptor Activation ◽  
The Novel ◽  
Structural Determinants ◽  
Inverse Agonists ◽  
Neurotensin Receptor ◽  
Small Molecule Ligands ◽  
Neurotensin Receptor 1 ◽  
G Protein Coupled

Neurotensin receptor 1 (NTSR1) and related G protein–coupled receptors of the ghrelin family are clinically unexploited, and several mechanistic aspects of their activation and inactivation have remained unclear. Enabled by a new crystallization design, we present five new structures: apo-state NTSR1 as well as complexes with nonpeptide inverse agonists SR48692 and SR142948A, partial agonist RTI-3a, and the novel full agonist SRI-9829, providing structural rationales on how ligands modulate NTSR1. The inverse agonists favor a large extracellular opening of helices VI and VII, undescribed so far for NTSR1, causing a constriction of the intracellular portion. In contrast, the full and partial agonists induce a binding site contraction, and their efficacy correlates with the ability to mimic the binding mode of the endogenous agonist neurotensin. Providing evidence of helical and side-chain rearrangements modulating receptor activation, our structural and functional data expand the mechanistic understanding of NTSR1 and potentially other peptidergic receptors.

scholarly journals Design, Synthesis, and Evaluation of Functionalized 5-(4-arylpiperazin-1-yl)-N-Quinolinyl-pentanamides as Selective Dopamine D3 Receptor Ligands

2021 ◽  
Author(s):  
Benjamin E Blass ◽  
Peng-Jen Chen ◽  
Michelle Taylor ◽  
Suzy A Griffin ◽  
John C Gordon ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Receptor Ligands ◽  
Design Synthesis ◽  
Amino Acid Homology ◽  
Affinity Ligands ◽  
The Central Nervous System ◽  
Dopamine D3 ◽  
Physiological Impact ◽  
G Protein Coupled ◽  
Selective Dopamine

Abstract Dopamine (1) plays a key role in normal physiological pathways in both the central nervous system and the periphery. The physiological impact of this neurotransmitter is mediated through its interaction with family of G-protein-coupled receptors (GPCRs). These receptors are designated as D1, D2, D3, D4, and D5 and divided into two sub-families, the D1-like sub-family (D1 and D5) and D2-like sub-family (D2, D3 and D4) based on pharmacological properties, amino acid homology, and genetic organization. Aberrant D3 activity has been linked to multiple diseases and conditions such as depression, schizophrenia, substance use disorder, inflammatory diseases, and Parkinson’s disease (PD). As part of our on-going program focused on the identification of novel D3 ligands, we have identified a novel series of 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides that are high affinity ligands for this receptor.

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