title: Oral bioavailability of a new class of micro-opioid receptor agonists containing 3,6-bis[Dmt-NH(CH(2))(n)]-2(1H)-pyrazinone with central-mediated analgesia.
abstract: The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioid-mimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-l-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH(2))(n)]-2(1H)-pyrazinones. These compounds displayed high micro-opioid receptor affinity (K(i)micro = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)micro = 204-307) and functional micro-opioid receptor agonism (guinea-pig ileum, IC(50) = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, i.c.v.) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7'), lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.
authors.affiliation: Medicinal Chemistry Group, LCBRA, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Shiotani
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Toshio
authors.initials: T
authors.lastname: Yokoi
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: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism; D013552:Swine; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C108102:2-(2'-(methylthio)ethyl)methionine; D000700:Analgesics; D011719:Pyrazines; D017450:Receptors, Opioid, mu; D008715:Methionine