Selective opioid dipeptides.
The surprising change of selectivity induced by the change of chirality in peptides containing the tetrahydro-3-isoquinoline carboxylic acid (Tic) in second position, interpreted as a conformational preference induced on the Tyr-Xaa-Phe domain, can instead be attributed to the Tyr-Tic message domain. The relative spatial disposition of the aromatic ring of delta-selective non peptidic opiates is compatible with a message domain, in opioid peptides, of only two residues. This hypothesis was tested through the synthesis of Tyr-L-Tic-NH2, Tyr-D-Tic-NH2, Tyr-L-Tic-Ala-NH2, Tyr-L-Tic-Ala-OH and Tyr-D-Tic-Ala-NH2. Peptides containing Tyr-L-Tic- behave as very selective delta antagonists and those containing Tyr-DTic- as non selective agonists. This is the first case of opioid peptides containing a two-residue message domain and of opioid dipeptides with substantial opioid activity.
Temussi
P A
PA
Dipartimento di Chimica, Università di Napoli Federico II, Italy.
Salvadori
S
S
Amodeo
P
P
Bianchi
C
C
Guerrini
R
R
Tomatis
R
R
Lazarus
L H
LH
Picone
D
D
Tancredi
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009294:Narcotics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D044005:Tetrahydroisoquinolines
D004151:Dipeptides; D004745:Enkephalins; D007546:Isoquinolines; D009294:Narcotics; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060208:deltorphin I, Ala(2)-; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D020881:Enkephalin, D-Penicillamine (2,5)-