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
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. 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: firstname.lastname@example.org Phone: 301-435-4074 Fax: 301-402-0220