An attempt to structurally convert mu-selective morphine toward delta-receptor binding: dimerization based on enkephalin conformation.
In order to elucidate the substrate specificities for mu- and delta-opioid receptors, dimerization of the mu-specific morphine molecule was attempted, based on the hypothesis of the possible relationship between the molecular conformation of endogenous enkephalin and its selectivity for each opioid receptor. The NOR2 ([normorphine]N-CH2-CH2-N[normorphine]) thus synthesized exhibited agonist activity showing a preference for binding with the delta-opioid receptor, compared with the parent morphine molecule. Antagonist activity was also observed for NOR3 ([normorphine]N-CH2-CH2-CH2-N[normorphine]).
Yara
H
H
Osaka University of Pharmaceutical Sciences, Japan.
Katagawa
Y
Y
Doi
M
M
Ishida
T
T
Inoue
M
M
Yasuda
M
M
Baba
A
A
Iwata
H
H
Kitamura
K
K
Sadatome
T
T
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014649:Vas Deferens / Q000187:drug effects
D004745:Enkephalins; D009022:Morphine Derivatives; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; C010616:normorphine