Synthesis, biological activity and NMR-based structural studies of deltorphin I analogues modified in message domain with a new ?,?-disubstituted glycines.
 

Synthesis, biological activity and NMR-based structural studies of deltorphin I analogues modified in message domain with a new ?,?-disubstituted glycines.

Related Articles Synthesis, biological activity and NMR-based structural studies of deltorphin I analogues modified in message domain with a new ?,?-disubstituted glycines.

Chem Biol Drug Des. 2016 Jan 25;

Authors: Lasota A, Fr?czak O, Muchowska A, Nowakowski M, Maciejczyk M, Ejchart A, Olma A

Abstract
This paper describes new deltorphin I analogues in which phenylalanine residues were replaced by the corresponding (R) or (S)-?-benzyl-?-azidoalanine, ?-benzyl-?-(1-pyrrolidinyl)alanine, ?-benzyl-?-(1-piperidinyl)alanine and ?-benzyl-?-(4-morpholinyl)-alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in the rat brain using [(3) H]DAMGO (a ? ligand) and [(3) H]DELT (a ? ligand). The affinity of analogues containing (R) or (S)-?-benzyl-?-azidoalanine in position 3 to ?-receptors strongly depended on the chirality of the ?,?-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-?-benzyl-?-(1-piperidinyl)Ala, which display the opposite selectivity, was analyzed by (1) H and (13) C NMR. The ?-selective Tyr-D-Ala-(R)-?-benzyl-?-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the ?-selective Tyr-D-Ala-(S)-?-benzyl-?-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 . Our results support the proposal that differences between ?- and ?-selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N-terminal message domain and the C-terminal address domain. This article is protected by copyright. All rights reserved.


PMID: 26808639 [PubMed - as supplied by publisher]



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