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Structure-based evolution of subtype-selective neurotensin receptor ligands.

ABSTRACT: Subtype-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 ?-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 ?(2)-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)-propionyl(11)]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.

SUBMITTER: Schaab C

PROVIDER: S-EPMC4234217 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Structure-based evolution of subtype-selective neurotensin receptor ligands.

Schaab Carolin C Kling Ralf Christian RC Einsiedel Jürgen J Hübner Harald H Clark Tim T Seebach Dieter D Gmeiner Peter P

ChemistryOpen 20140923 5

Subtype-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), ...[more]

PMID: 25478316

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Dataset Information

Structure-based evolution of subtype-selective neurotensin receptor ligands.

Publications

Structure-based evolution of subtype-selective neurotensin receptor ligands.

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