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Potent Pharmacophoric Delta- and Mu-Opioid Receptor Antagonists and Conversion of Endomorphin Mu-Opioid Agonists to Antagonists

Posted Apr 30 2006 5:00pm

Description of Invention:
The inhibition (antagonism) of mu-opioid receptors is a critical human health topic, since this receptor is the key element in the neural reward pathway in the central nervous system responsible for craving and addiction to food, alcohol or various drugs, such as morphine and its derivatives. Furthermore, antagonists to these receptors are absent in nature. This invention provides compositions for new modified opioid antagonists.

For example, a series of dimeric N,N-dimethyl-Dmt-Tic (2’,6’-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) analogues were covalently linked tail-to-tail through diaminoalkane, and symmetric or asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. The latter compounds exhibit dual antagonism toward delta- and mu-opioid receptors providing a means to simultaneously regulate two independent opioid receptors to combat addiction, tolerance, and alcohol dependency. Dmt is the essential pluripotent amino acid residue that regulates binding to all opioid receptor molecules, which are classified into delta, mu, and kappa subtypes depending on the type of interacting opioid. Compounds from another class of mu-opioid antagonists were also prepared, including [N-allyl-Dmt1]endomorphin-1 (N-allyl-Dmt-Pro-Trp-Phe-NH2) and [N-allyl-Dmt1]endomorphin-2 (N-allyl-Dmt-Pro-Phe-Phe-NH2).

The former set of dimeric compounds readily pass through the epithelial barriers in the gut and brain when injected systematically or taken orally. Additionally, these bivalent ligands would be attractive in drug design due to their stability to proteolytic degradation. That they are also slightly more hydrophobic may increase potency by their ability to transit membranes.

Applications:
Potential opiate, food and alcohol addiction therapeutics

Development Status:
Early stage

Inventors:
Lawrence H Lazarus (NIEHS)


Patent Status:
HHS, Reference No. E-305-2005/0
US, Application No. 12/065,121 filed 28 Feb 2008


Relevant Publication:
  1. T Li et al. Potent Dmt-Tic pharmacophoric delta- and mu-opioid receptor antagonists. J Med Chem. 2005 Dec 15;48(25):8035-8044. [ PubMed abs ]
  2. T Li et al. New series of potent delta-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif. Bioorg Med Chem Lett. 2005 Dec 15;15(24):5517-5520. [ PubMed abs ]


Licensing Status:
This technology is available for exclusive, co-exclusive, or nonexclusive licensing.


Portfolios:
Central Nervous System
Central Nervous System - Therapeutics



For Additional Information Please Contact:
Steven Standley Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: sstand@mail.nih.gov
Phone: 301-435-4074
Fax: 301-402-0220


Ref No: 1346

Updated: 05/2006

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