Dimeric enkephalins display enhanced affinity and selectivity for the delta opiate receptor
Shimohigashi, Y.; Costa, T.; Matsuura, S.; Chen, H.C.; Rodbard, D.
Molecular Pharmacology 21(3): 558-563
1982
ISSN/ISBN: 0026-895X PMID: 6287194 Document Number: 192315
A series of dimeric analogs of [D-Ala2,Leu5]enkephalin, cross-linked at the COOH terminus by .alpha.,.omega.-diaminoalkanes of variable length, was synthesized. The structure of the purified peptides was confirmed by amino acid analysis and by MW determination using mass spectrometry. The peptides were evaluated for activity in 3 radioligand assay systems, employing membranes from rat brain, using [3H]naloxone, 125I-[D-Ala2,D-Leu5]enkephalin and 3H-[D-Ala2,Met5]enkephalin amide, to evaluate activity for .mu. and .delta. opiate receptors. The dimeric pentapeptide enkephalin analogs were less potent than the monomeric analog ([D-Ala2,Leu5]enkephalin amide) when [3H]naloxone was used as the labeled ligand, but showed a striking increase in relative potency when 125I-[D-Ala2,D-Leu5]enkephalin was utilized as tracer, indicating selectivity for the .delta. receptors. Relative activity was highest when the cross-linking methylene bridge consisted of n = 2, 4 or 6 C atoms and decreased dramatically for longer chain lenghs (n = 8, 10 or 12). The selectivity of the compounds for the .delta. receptors appeared to be greatest when n = 2 and decreased progressively as the length of the methylene bridge was increased. Dimeric pentapeptide enkephalins apparently have increased affinity and selectivity for the .delta. receptor. The dimeric enkephalins may cross-link opiate receptors. The peptides provide a new class of compounds for the study of opiate-receptor pharmacology.