Conformational analysis of potent and very selective delta opioid dipeptide antagonists.

Abstract

The delta 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 Tyr1 with 2,6-dimethyl-L-tyrosyl (Dmt). Dmt-Tic-NH2, Dmt-Tic-OH, Dmt-Tic-Ala-NH2 and Dmt-Tic-Ala-OH are all more active and/or selective than the corresponding [Tyr1]-parent peptides. In fact the selectivities of Dmt-Tic-OH and Dmt-Tic-Ala-OH are the highest ever recorded for opioid molecules. 1H 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-NH2 shows that these conformers have a shape very similar to that of the bioactive conformation of Tyr-Tic-NH2 and to that of naltrindole.

• Authors: P Amodeo, G Balboni, O Crescenzi, R Guerrini, D Picone, S Salvadori, T Tancredi, P A Temussi
• Journal: FEBS letters (FEBS Lett) Vol. 377 Issue 3 Pg. 363-7 (Dec 27 1995) ISSN: 0014-5793 [Print] England
• PMID: 8549756 (Publication Type: Journal Article)

Chemical References

• Dipeptides
• Isoquinolines
• Receptors, Opioid, delta
• Tetrahydroisoquinolines
• 2',6'-dimethyltyrosine
• 1,2,3,4-tetrahydroisoquinoline carboxylic acid
• Tyrosine

Topics

• Dipeptides (chemistry, metabolism, pharmacology)
• Drug Design
• Isomerism
• Isoquinolines (chemistry)
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Molecular Conformation
• Receptors, Opioid, delta (antagonists & inhibitors, metabolism)
• Tetrahydroisoquinolines
• Tyrosine (analogs & derivatives, chemistry)