Novel Dmt-Tic Analogues Specific for Delta- and Mu-Opioid ReceptorsA 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.
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. 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 pain with the elimination of drug tolerance.
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 reducing tolerance to morphine. 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.
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