Conformational analysis of potent and very selective delta opioid dipeptide antagonists.
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.
Amodeo
P
P
ICMIB del CNR, Arco Felice, Napoli, Italy.
Balboni
G
G
Crescenzi
O
O
Guerrini
R
R
Picone
D
D
Salvadori
S
S
Tancredi
T
T
Temussi
P A
PA
D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D007536:Isomerism; D007546:Isoquinolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
D004151:Dipeptides; D007546:Isoquinolines; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C076121:2',6'-dimethyltyrosine; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D014443:Tyrosine