Structure-activity relationships of the delta-opioid-selective agonists, deltorphins.
Deltorphins are naturally occurring peptides with high affinity and selectivity for delta-opioid receptors. They share with dermorphin, another mu-selective opioid agonist, the same N-terminal tripeptide Tyr-D-Xaa-Phe, where D-Xaa is a D-Ala or a D-Met residue. This common sequence appears to be essential for the best fitting of the peptides to both mu- or delta-opioid sites. We studied the changes in receptor affinity and selectivity and in biological potency of deltorphins due to shortening of the sequence, C-terminal deamidation or single amino acid substitutions. The results support the view that a code addressing the molecule towards delta-opioid sites is expressed in the C-terminal region of these peptides. This addressing domain confers high delta-selectivity to the ligand in the following two ways: (i) increased affinity for delta-sites; (ii) decreased affinity for mu-sites. The sequence of the C-terminal tripeptide appears to be responsible for the high delta-affinity of the molecules. Negatively charged side chains inhibit mu-binding and enhance delta-selectivity.
Melchiorri
P
P
Institute of Pharmacology, University La Sapienza, Rome, Italy.
Negri
L
L
Falconieri-Erspamer
G
G
Severini
C
C
Corsi
R
R
Soaje
M
M
Erspamer
V
V
Barra
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism* / Q000494:pharmacology; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D009842:Oligopeptides; D010455:Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin