Receptor binding and biological activity of the dermorphin analog Tyr-D-Arg(2)-Phe-Sar (TAPS).
The binding of Tyr-D-Arg(2)-Phe-sarcosine(Sar)(4) (TAPS), a proposed mu-opioid receptor-selective tetrapeptide analog of dermorphin to opioid receptors, was studied using selective binding assays for subtypes of mu-, delta- and kappa-opioid receptors. Subtype specific mu-opioid receptor binding was further characterized in the presence of sodium and guanosine nucleotides and the activity of TAPS in isolated guinea pig ileum was compared to other mu-opioid receptor-selective ligands. Further, the antinociceptive properties of TAPS following intrathecal (i.t.) administration in rats, as a model of spinal antinociception, were evaluated. The K(i)-values for TAPS at the mu(1)- and mu(2)-opioid receptor sites were 0.4 and 1.3 nM, respectively, suggesting high affinity binding to mu-opioid receptor binding sites with an increased selectivity to mu(1)-opioid receptor sites. The attenuated reduction of TAPS binding at the mu(2)-opioid receptor subtype in the presence of the stable guanosintriphosphate analog 5'-guanylylimidodiphosphate and sodium suggests a potential partial antagonist mode of action at this site.
Department of Cardiology and Pulmonology, Zentrum Innere Medizin, University of Göttingen, Germany. svonhof@gwdg.de
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S
Vonhof
F C
FC
Barone
W J
WJ
Price
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Paakkari
J H
JH
Millison
G Z
GZ
Feuerstein
A K
AK
Sirén
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018847:Opioid Peptides; D012123:Pulmonary Ventilation / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013997:Time Factors
D000700:Analgesics; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; C030058:dermorphin; D009270:Naloxone; C034643:naloxonazine; C053418:tyrosyl-arginyl-phenylalanyl-sarcosine