[The effect of modification of the carboxyl group in short D-arginine 2-containing enkephalin analogs on their affinity and selectivity for opiate receptors].
Radioreceptor binding assay using a membrane fraction from the rat brain was applied to study [D-Arg2, Leu5] enkephalin and two series of its analogues truncated at the C-terminus with a free or modified carboxyl group: tetra- and tripeptide amides and ethyl esters. The affinity to mu-specific opiate receptor subtype of the N-terminal [D-Arg2] tetrapeptide ethyl ester was 44 times as high as that of the tripeptide with a free carboxyl, and thus the ester retained up to 10% of leucine-enkephalin binding potency. However, a comparable esterification of the carboxyl group in the N-terminal [D-Arg2] tripeptide led to a 6-fold reduction in its affinity to mu-receptors. Consequently, identical modifications of the C-terminal carboxyl group in enkephalin analogues of various length can have completely different effects. Substitution of the natural glycine residue by D-arginine residue in position 2 of the enkephalin molecule truncated at the C-terminus increased the mu-receptor binding potency of the tetrapeptide, whereas its delta receptor binding potency declined by more than one order of magnitude. Simultaneous replacement of glycine2 by D-arginine2 and carboxyl amidation resulted in the short enkephalin analogue Tyr--D--Arg--Gly--Phe--NH2, whose affinity to mu receptors was four times as high as that of leucine--enkephalin, the tetrapeptide being 284 times more selective for the mu vs. delta opiate receptors.
Inkina
N M
NM
Rozental'
G F
GF
Bobrova
I V
IV
Chipens
G I
GI
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009270:Naloxone / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*
D008024:Ligands; D011957:Receptors, Opioid; D009270:Naloxone; D004743:Enkephalin, Leucine; C066412:enkephalin, Arg(2)-Leu(5)-
Vliianie modifikatsii karboksil'noĭ gruppy ukorochennykh D-arginin 2-soderzhashchikh analogov énkefalina na ikh srodstvo i izbiratel'nost' k opiatnym retseptoram.