New series of potent delta-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif.
Heterodimeric compounds H-Dmt-Tic-NH-hexyl-NH-R (R=Dmt, Tic, and Phe) exhibited high affinity to delta- (K(i)delta=0.13-0.89nM) and mu-opioid receptors (K(i)mu=0.38-2.81nM) with extraordinary potent delta antagonism (pA(2)=10.2-10.4). These compounds represent the prototype for a new class of structural homologues lacking mu-opioid receptor-associated agonism (IC(50)=1.6-5.8muM) based on the framework of bis-[H-Dmt-NH]-alkyl (Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem.2003, 46, 3201), which exhibited both high mu affinity and bioactivity.
Li
Tingyou
T
The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
Shiotani
Kimitaka
K
Miyazaki
Anna
A
Fujita
Yoshio
Y
Tsuda
Yuko
Y
Ambo
Akihiro
A
Sasaki
Yusuke
Y
Jinsmaa
Yunden
Y
Marczak
Ewa
E
Bryant
Sharon D
SD
Lazarus
Lawrence H
LH
Okada
Yoshio
Y
D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu