Increased affinity and selectivity of enkephalin tripeptide (Tyr-D-Ala-Gly) dimers.
The binding of alkylendiamide dimers of the three N-terminal residues of [D-Ala2,D-Leu5]enkephalin (DADL) to rat brain and Ng108-15 neuroblastoma-glioma cell membranes was compared with that of DADL, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) and morphiceptin. Tritiated DADL and DAGO were used as labeled ligands for delta- and mu-receptors, respectively. Dimerization of the tripeptides resulted in dramatic increases in both mu and delta binding. The binding to mu-receptors showed two peaks at an alkyl chain length of n = 2 and approximately n = 16. In contrast, delta binding (NG108-15 cells) increased steadily with increasing chain length. The dimers with n less than 18 were mu-preferential, and the one with n = 2 showed the most dramatic increase in mu selectivity with a 400 fold higher affinity to mu- than to delta-receptors. For long-chain alkyl spacers the compounds became delta selective.
Lutz
R A
RA
Cruciani
R A
RA
Shimohigashi
Y
Y
Costa
T
T
Kassis
S
S
Munson
P J
PJ
Rodbard
D
D
D000818:Animals; D001921:Brain / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
D004745:Enkephalins; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu