[D-Pen2,D-Pen5]enkephalin analogues with increased affinity and selectivity for delta opioid receptors.
The conformationally restricted, cyclic disulfide-containing enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by halogenation (F, Cl, Br, I) of the phenylalanine-4 residue in the para position. The potency and selectivity of these analogues for the delta opioid receptor was greater than that of the parent peptide. The analogues possessed greater potency and affinity for the delta receptors than DPDPE in the mouse vas deferens assay and in radioreceptor assays (against [3H]DPDPE), respectively. [p-ClPhe4]DPDPE was the most selective in the radioligand binding assays (IC50(mu)/IC50(delta) = 574), being about 5-fold more delta opioid receptor selective than DPDPE in this assay, whereas [p-IPhe4]DPDPE was the most selective in the classical bioassay systems using the mouse vas deferens and guinea pig ileum assays (IC50(GPI)/IC50(MVD) = 17,374), making it nearly 9-fold more selective than DPDPE in direct comparisons using the same assay conditions.
Toth
G
G
Department of Chemistry, University of Arizona, Tucson 85721.
Kramer
T H
TH
Knapp
R
R
Lui
G
G
Davis
P
P
Burks
T F
TF
Yamamura
H I
HI
Hruby
V J
VJ
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000502:physiology
D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D020881:Enkephalin, D-Penicillamine (2,5)-