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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), we replaced the tyrosine unit by β 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 n m ) 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.

Structure‐Based Evolution of Subtype‐Selective Neurotensin Receptor Ligands