Novel Dmt-Tic Analogues Specific for Delta- and Mu-Opioid Receptors
Description of Invention:
Opioid receptor modulators, used historically for pain control, have more recently been shown to possess broader therapeutic potential in areas such as opiate and alcohol abuse, neurological disease or injury, neuropeptide or neurotransmitter imbalance, and immune system dysfunction. Furthermore, their interaction with key reward pathways presents interesting avenues for exploration in the treatment of food as an addictive substance, due to the fact that obesity is a major health problem in the U.S. Also, evidence of modulatory interactions between delta- and mu-opioid receptors has spurred interest in new opioid ligands possessing mixed and dual specificity for these receptors. These bifunctional compounds are particularly promising for treatment of addiction and treatment of pain with the elimination of drug tolerance.
The inventors have developed a wide variety of highly selective Dmt-Tic analogues with potential therapeutic applications. These analogues include specific agonists and antagonists of the delta- and mu-opioid receptors and combinations thereof.
Some disclosed analogues are di- and tri-peptidic derivatives of the Dmt-Tic pharmacophore; in addition to opioid receptor specificity, two of these derivatives have been shown to inhibit the activity of human multidrug resistance glycoprotein 1 (hMDR1) and may represent a novel chemosensitizing agent for treating cancer, and may also be used for reducing tolerance to morphine, the drug of choice in most hospitals around the world, thereby increasing its effectiveness. Also disclosed are compounds produced through derivatization of Dmt-Tic reference compounds with lysine, resulting in an unexpected and broad range of delta- and/or mu-opioid receptor modulation. The inventors have also prepared symmetric and asymmetric Dmt-Tic di-peptides that are potent dual delta- and mu-opioid receptor antagonists and that can pass through the gastrointestinal and blood-brain barriers. Finally, the inventors have prepared various fluorescent Dmt-Tic analogs that are useful for study of delta- and mu-opioid receptor structure and function.
Applications:
Potential opiate, food, and alcohol addiction therapeutics.
Potential therapeutics for pain treatment.
Potential therapeutics for cancer.
Tools for screening ligand binding activity and differentiating between delta- and mu-opioid receptors.
Market:
In 2004, approximately 22 million Americans over the age of 12 required treatment for alcohol or illicit drug abuse and addiction; 13 million of these were classified as alcoholics.
Approximately 50 million Americans suffer from pain, and an estimated 1.5 billion people suffer from moderate to severe pain worldwide.
Two-thirds of the U.S. population is overweight, with a quarter designated as obese (9 million of whom are children); the number of overweight Americans doubled between 1980-1999 and is predicted to increase 20% by 2013 to 140 million.
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T Lovekamp et al. Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent delta-opioid antagonist. Brain Res. 2001 May 25;902(1):131-134. [PubMed abs]
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]
T Li et al. Transformation of a mu-opioid agonist into biologically potent mu-opioid antagonists. Bioorg Med Chem. 2007 Feb 1;15(3):1237-1251. [PubMed abs]
G Balboni et al. Highly selective fluorescent analogue of the potent delta-opioid receptor antagonist Dmt-Tic. J Med Chem. 2004 Dec 16:47(26):6541-6546. [PubMed abs]
Licensing Status: Available for exclusive or nonexclusive licensing.
Portfolios: Internal Medicine Central Nervous System Cancer
Central Nervous System -Therapeutics-Psychotherapeutics-Antidepressants Central Nervous System -Therapeutics-Psychotherapeutics-Drug Dependence Cancer -Therapeutics Central Nervous System -Therapeutics Internal Medicine-Therapeutics
For Additional Information Please Contact: Charlene A. Sydnor Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301/435-4689
Email: sydnorc@mail.nih.gov
Fax: 301/402-0220
