Distribution and analgesia of [3H][D-Pen2, D-Pen5]enkephalin and two halogenated analogs after intravenous administration.
To improve pharmacological characteristics of the delta-selective, cyclic peptide [D-Pen2, D-Pen5]enkephalin (DPDPE), modification by halogenation at the Phe4 residue was undertaken. The present study was to determine the extent [3H]DPDPE, [3H][p-Cl-Phe4]DPDPE and [p-125IPhe4]DPDPE crosses the blood-brain barrier, elicits analgesia and to characterize selective organ distribution and stability after i.v. administration. A significantly greater percentage of total [3H][p-Cl-Phe4]DPDPE reached the brain after 10, 20 and 40 min as compared to [3H]DPDPE and both peptides were significantly displaced by pretreatment with naloxone or naltrindole. The amount of [3H]DPDPE detected in the brain was greater than that of [p-125IPhe4]DPDPE. Distribution results revealed large amounts of the administered peptides were sequestered rapidly in the gall bladder and secreted into the small intestine. Hot-plate antinociception tests 5 min after i.v. administration (30 and 60 mg/kg) revealed [p-Cl-Phe4]DPDPE to elicit a much greater analgesic effect as compared to DPDPE or [p-125IPhe4]DPDPE. These results provide evidence that [p-Cl-Phe4]DPDPE has a greater apparent distribution to the brain and has a greater effect on the antinociception threshold as tested on the hot-plate than DPDPE or [p-125IPhe4]DPDPE. Stability of unlabeled and tritiated DPDPE and [p-Cl-Phe4]DPDPE was determined both in vitro and in vivo; both unlabeled and tritiated DPDPE and [p-Cl-Phe4]DPDPE remain intact.
Weber
S J
SJ
Department of Pharmacology, University of Arizona, Tucson.
Greene
D L
DL
Sharma
S D
SD
Yamamura
H I
HI
Kramer
T H
TH
Burks
T F
TF
Hruby
V J
VJ
Hersh
L B
LB
Davis
T P
TP
D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D004355:Drug Stability; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000493:pharmacokinetics* / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009019:Morphinans / Q000378:metabolism; D009270:Naloxone / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives*; D015260:Neprilysin / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D000700:Analgesics; D004745:Enkephalins; D007211:Indoles; D009019:Morphinans; D014316:Tritium; C064219:enkephalin, Pen(2,5)-4-chloro-Phe(4)-; C070930:enkephalin, Pen(2,5)-4'-iodo-Phe(4)-; D009270:Naloxone; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D015260:Neprilysin; C055382:naltrindole