title: Unique high-affinity synthetic mu-opioid receptor agonists with central- and systemic-mediated analgesia.
abstract: 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.
authors.affiliation: 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
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Toshio
authors.initials: T
authors.lastname: Yokoi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Ryoji
authors.initials: R
authors.lastname: Konishi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nagata
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: 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
chemical_list: D000700:Analgesics; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014443:Tyrosine