Unique high-affinity synthetic mu-opioid receptor agonists with central- and systemic-mediated analgesia.
Unique opioid mimetic substances containing identical N-terminal aromatic residues separated by an unbranched alkyl chain containing two to eight methylene groups were developed. Regardless of the length of interposing alkyl chain, the bis-Tyr and bis-Phe compounds were inactive; however, replacement by a single Dmt (2',6'-dimethyl-L-tyrosine) residue enhanced activity by orders of magnitude. Moreover, the bis-Dmt compounds were another 10-fold more potent with an optimum intra-aromatic ring distance of about four to six methylene units. 1,4-Bis(Dmt-NH)butane (7) had high mu-opioid receptor affinity (K(i) = 0.041 nM) and functional mu-opioid agonist bioactivity (IC(50) = 5.3 nM) with in vivo central (intracerebroventricular) and systemic (subcutaneous) analgesia in mice (1.5- to 2.5-fold greater than and 10-12% relative to morphine, respectively); these activities were reversed by naloxone to the same degree. It appears that the bis-Dmt compounds indiscriminately act as both message and address domains.
Okada
Yoshio
Y
Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry and High Technology Research Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan. lazarus@niehs.nih.gov
Tsuda
Yuko
Y
Fujita
Yoshio
Y
Yokoi
Toshio
T
Sasaki
Yusuke
Y
Ambo
Akihiro
A
Konishi
Ryoji
R
Nagata
Mitsuhiro
M
Salvadori
Severo
S
Jinsmaa
Yunden
Y
Bryant
Sharon D
SD
Lazarus
Lawrence H
LH
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D009294:Narcotics / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014649:Vas Deferens / Q000378:metabolism / Q000502:physiology
D000700:Analgesics; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014443:Tyrosine