of Work: The analgesic activity of recently developed opioidmimetic substances was determined in vivo in mice in comparison to morphine and using specific opiate-receptor antagonists to assess their mode of action. The antinociception profile paralleled that of the in vitro functional pharmacological data (GPI,guinea-pig ileum and MVD, mouse vas deferens), and reflected the opioid-receptor binding affinity (see, Project 1 for details on the interaction of compounds with delta- and mu-opioid receptors). A series of novel Dmt-containing alkyl and alkyl pyrazinone group as opioidmimetic compounds had exceptional activity in vivo. In particular, one of which was 60- to 71-fold more potent than morphine in generating analgesia by the tail-flick test after i.c.v. administration; the spinal (tail-flick test) is more potent than the supraspinal effects (hot-plate test) by a factor of 2-3. In particular, the compound 3-[4'-Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)pyrazinone had very high affinity (Ki mu = 0.02 nM), selectivity (delta/mu = 1,520) and agonist activity (GPI, IC50 = 1.7 nM) with weak activity toward the delta receptor in all assay systems. This compound acted to produce spinal antinociception primarily through spinal antinociception using the mu-2 receptor subtype; however, the mu-1 subtype dominates supraspinally. The s.c. injection produced CNS-mediated antinociception, providing evidence the compound passed through membrane barriers in both the gastrointestinal epithelium and in the microcapillary tight junctions that regulate the blood-brain barrier (BBB). However, a tolerance was obtained after a week of daily injections that was equivalent to morphine and suggests that both substances act through similar mechanisms at mu-opioid receptors. Another class of Dmt-containing pyrazinone compounds, the 3,6-bis-[Dmt-NH-(CH2)n]-2(1H)-pyrazinone compounds not only exhibited central (CNS) mediated analgesia, but also were orally bioavailable opioid mimetics. These symmetric substances displayed high affinity for mu-opioid receptors (Ki = 0.04-0.12 nM) and potent angonism on GPI (IC50 = 1.3-1.9 nM). They produced analgesia in vivo by i.c.v. administration that was 50- to 63-fold more potent than morphine, but only about half as potent when injected s.c. or administered orally, which is still orders of magnitude greater than other endogenous opioid peptides and, importantly, were unmodified by glycosylation, adamantane, triglycerides, halogens, antibody, biotin, bulky organic molecules, esterification of a C-terminal carboxyl group (of which none exist in these compounds) or O-acylation of the phenolic hydroxyal group of Tyr or Dmt, nor was it necessary to absorb them onto polysorbate coated nanoparticles to induced uptake through the BBB. Studies a group of mu opioid substances containing Dmt in lieu of Tyr in endomorphins-1 and -2 revealed differences in their mode of action that also serve to differential these stucturally related compounds. Whereas both compounds exhibited potent analgesia, their mode of action and degree of analgesia was significantly different. Dmt enhanced all measured parameters of activity by orders of magnitude both in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES100472-04
Application #
7170022
Study Section
(LCBR)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2005
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lazarus, Lawrence H; Okada, Yoshio (2012) Engineering endomorphin drugs: state of the art. Expert Opin Ther Pat 22:1-14
Marczak, Ewa D; Jinsmaa, Yunden; Myers, Page H et al. (2009) Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent mu/delta-opioid receptor antagonist, regulates obese-related factors in mice. Eur J Pharmacol 616:115-21
Balboni, Gianfranco; Trapella, Claudio; Sasaki, Yusuke et al. (2009) Influence of the side chain next to C-terminal benzimidazole in opioid pseudopeptides containing the Dmt-Tic pharmacophore. J Med Chem 52:5556-9
Vergura, Raffaella; Balboni, Gianfranco; Spagnolo, Barbara et al. (2008) Anxiolytic- and antidepressant-like activities of H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), a novel selective delta opioid receptor agonist. Peptides 29:93-103
Jinsmaa, Yunden; Marczak, Ewa D; Balboni, Gianfranco et al. (2008) Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph. Pharmacol Biochem Behav 90:651-7
Balboni, Gianfranco; Fiorini, Stella; Baldisserotto, Anna et al. (2008) Further studies on lead compounds containing the opioid pharmacophore Dmt-Tic. J Med Chem 51:5109-17
Koda, Yasuko; Del Borgo, Mark; Wessling, Susanne T et al. (2008) Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides. Bioorg Med Chem 16:6286-96
Salvadori, Severo; Fiorini, Stella; Trapella, Claudio et al. (2008) Role of benzimidazole (Bid) in the delta-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH(2)-Bid (UFP-502). Bioorg Med Chem 16:3032-8
Ryu, Eun Kyoung; Wu, Zhanhong; Chen, Kai et al. (2008) Synthesis of a potent and selective (18)F-labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging. J Med Chem 51:1817-23
Balboni, Gianfranco; Onnis, Valentina; Congiu, Cenzo et al. (2007) Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore. Bioorg Med Chem 15:3143-51

Showing the most recent 10 out of 38 publications