title: Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists.
abstract: N-Allylation (-CH(2)-CHCH(2)) of [Dmt(1)]endomorphins yielded the following: (i) [N-allyl-Dmt(1)]endomorphin-2 (Dmt=2',6'-dimethyl-l-tyrosine) (12) and [N-allyl-Dmt(1)]endomorphin-1 (15) (K(i)mu=0.45 and 0.26nM, respectively) became mu-antagonists (pA(2)=8.59 and 8.18, respectively) with weak delta-antagonism (pA(2)=6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD(50) (0.148ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P=0.0055). Similarly, N-allylation of the potent mu-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into mu-antagonists (pA(2)=7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak delta-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics continues to provide a facile means to convert selective mu-opioid agonists into potent mu-opioid antagonists.
authors.affiliation: The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nedachi
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Ewa
authors.initials: E
authors.lastname: Marczak
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: H Scott
authors.initials: HS
authors.lastname: Swartzwelder
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000478:Alkylation; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine