Last update 01 Nov 2024

NTSR2 x μ opioid receptor

Last update 01 Nov 2024

Basic Info

Related Targets

NTSR2μ opioid receptor

Drugs associated with NTSR2 x μ opioid receptor

KGOP01

Target

NTSR2 x μ opioid receptor

Mechanism

NTSR2 agonists [+1]

Active Org.

Vrije Universiteit Brussel

Originator Org.

Vrije Universiteit Brussel

Active Indication

Pain

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NTSR2 x μ opioid receptor

100 Translational Medicine associated with NTSR2 x μ opioid receptor

0 Patents (Medical) associated with NTSR2 x μ opioid receptor

Literatures (Medical) associated with NTSR2 x μ opioid receptor

01 Jan 2019·Tremor and other hyperkinetic movements (New York, N.Y.)

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

Article

Author: Forlani, Sylvie ; Trouillard, Oriane ; Nava, Caroline ; Guegan, Justine ; Keren, Boris ; Krack, Paul ; Bouteiller, Delphine ; Hartmann, Andreas ; Brice, Alexis ; Durif, Franck ; Depienne, Christel ; Agid, Yves ; Roze, Emmanuel ; Vidailhet, Marie ; Damier, Philippe ; Anheim, Mathieu ; Leitão, Elsa ; Worbe, Yulia ; Marie, Yannick ; Ciura, Sorana ; Kabashi, Edor ; Viallet, François ; Houeto, Jean-Luc

BackgroundGenes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches.MethodsWe first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish.ResultsThirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development.DiscussionThese results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

01 Oct 2014·ChemistryOpenQ3 · CHEMISTRY

Structure‐Based Evolution of Subtype‐Selective Neurotensin Receptor Ligands

Q3 · CHEMISTRY

ArticleOA

Author: Seebach, Dieter ; Clark, Tim ; Hübner, Harald ; Gmeiner, Peter ; Kling, Ralf Christian ; Schaab, Carolin ; Einsiedel, Jürgen

AbstractSubtype‐selective agonists of the neurotensin receptor NTS2 represent a promising option for the treatment of neuropathic pain, as NTS2 is involved in the mediation of μ‐opioid‐independent anti‐nociceptive effects. Based on the crystal structure of the subtype NTS1 and previous structure–activity relationships (SARs) indicating a potential role for the sub‐pocket around Tyr11 of NT(8–13) in subtype‐specific ligand recognition, we have developed new NTS2‐selective ligands. Starting from NT(8–13), we replaced the tyrosine unit by β2‐amino acids (type 1), by heterocyclic tyrosine bioisosteres (type 2) and peptoid analogues (type 3). We were able to evolve an asymmetric synthesis of a 5‐substituted azaindolylalanine and its application as a bioisostere of tyrosine capable of enhancing NTS2 selectivity. The S‐configured test compound 2 a, [(S)‐3‐(pyrazolo[1,5‐a]pyridine‐5‐yl)‐propionyl11]NT(8–13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30‐fold NTS2 selectivity over NTS1. The (R)‐epimer 2 b showed lower NTS2 affinity but more than 600‐fold selectivity over NTS1.

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