of Work: Antinociception and antagonists to this activity by recently developed opioidmimetic substances was determined in vivo in mice in comparison to morphine (mu-opioid receptor agonist) and deltorpin (delta-opioid agonist) 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-Tic pharmacophoric drugs or protodrugs exhibited antagonism in vitro and in vivo using the hot-plate (supraspinal effects, the central nervous system) and tail-flick test (spinal effects). The control compounds exhibited central (CNS) mediated analgesia and were orally bioavailable opioidmimetics. ? ? Interestingly, the N,N-dimethyl-Dmt-Tic-NH-adamantane and -tert-butyl derivatives inhibited tolerance to morphine in mice, which suggests that the multidrug resistance P-glycoprotein 1 was involved in this observation due to the inhibition in vitro of Pg-1 by these opioid analogues. Other Dmt-Tic compounds, MZ-2, in particular (patent application pending) prevents the formation of tolerance to morphine and like the allylated endomorphines (infra vide), but in contrast act as dual antagonists to inhibit both delta- and mu-opioid activities. Furthermore, the elimination of tolerance occurred without the severe side-effects seen with both naloxone and naltrexone.? ? Studies on the mu opioid agonists 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. The N-allyl derivatives of both endomorphines were potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES100472-06
Application #
7593979
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2007
Total Cost
$297,505
Indirect Cost
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
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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
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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

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