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Conformational analysis of potent and very selective δ opioid dipeptide antagonists
Author(s) -
Pietro Amodeo,
Gianfranco Balboni,
Orlando Crescenzi,
Remo Guerrini,
Delia Picone,
Severo Salvadori,
Teodorico Tancredi,
Piero Andrea Temussi
Publication year - 1995
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(95)01374-1
Subject(s) - chemistry , conformational isomerism , dipeptide , stereochemistry , naltrindole , isoquinoline , selectivity , peptide , medicinal chemistry , molecule , opioid , opioid receptor , organic chemistry , receptor , biochemistry , catalysis
The δ selectivity and antagonism of peptides containing l ‐tetrahydro‐3‐isoquinoline carboxylic acid (Tic) in second position can be attributed mainly to the Tyr‐Tic unit. These properties can be further enhanced by substituting Tyr 1 with 2,6‐dimethyl‐ l ‐tyrosyl (Dmt). Dmt‐Tic‐NH 2 , Dmt‐Tic‐OH, Dmt‐Tic‐Ala‐NH 2 and Dmt‐Tic‐Ala‐OH are all more active and/or selective than the corresponding [Tyr 1 ]‐parent peptides. In fact the selectivities of Dmt‐Tic‐OH and Dmt‐Tic‐Ala‐OH are the highest ever recorded for opioid molecules. 1 H NMR spectra in a DMSO/water mixture at 278 K reveal the presence of two similar conformers, characterised by a cis or trans Dmt‐Tic bond, in all four peptides. A detailed conformational analysis in solution of Dmt‐Tic‐NH 2 shows that these conformers have a shape very similar to that of the bioactive conformation of Tyr‐Tic‐NH 2 and to that of naltrindole.