Opioid receptor selectivity alteration by single residue replacement: synthesis and activity profile of [Dmt1]deltorphin B.
The single amino acid replacement of 2',6'-dimethyl-L-tyrosine in deltorphin B (H-Dmt-D-Ala-Phe-Glu-Val-Val-Gly-NH2) yielded high affinity for mu- and delta-binding sites. [Dmt1]Deltorphin B lacks activity at kappa-opioid binding sites. Bioactivity in vitro with guinea-pig ileum confirmed that [Dmt1]deltorphin B interacted with mu-opioid receptors by reducing electrically induced contractions in a naloxone-reversible manner and was 150-fold more potent than morphine and comparable to [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO). The inhibition of spontaneous contractions of rabbit jejunum provided evidence for delta-opioid receptor interaction. Analgesia (hot plate and tail flick tests) revealed that [Dmt1]deltorphin B was 180- to 200-fold more potent than morphine. Pretreatment with naloxone, naltrindole or H-Dmt-Tic-Ala-OH (a highly selective delta-opioid receptor antagonist) prevented [Dmt1]deltorphin B antinociception. Thus, [Dmt1]deltorphin B exhibited remarkably high dual affinity and bioactivity toward delta- and mu-opioid receptors.
Guerrini
R
R
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Capasso
A
A
Sorrentino
L
L
Anacardio
R
R
Bryant
S D
SD
Lazarus
L H
LH
Attila
M
M
Salvadori
S
S
D000818:Animals; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*
D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin; D009270:Naloxone; D009271:Naltrexone; C055382:naltrindole