|Title||Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Giri AKumar, Apostol CR, Wang Y, Forte BL, Largent-Milnes TM, Davis P, Rankin D, Molnar G, Olson KM, Porreca F, Vanderah TW, Hruby VJ|
|Journal||J Med Chem|
|Date Published||2015 Nov 12|
|Keywords||Amino Acid Sequence, Analgesics, Animals, HEK293 Cells, Humans, Male, Mice, Neurokinin-1 Receptor Antagonists, Pain, Peptides, Rats, Receptors, Neurokinin-1, Receptors, Opioid, Receptors, Opioid, delta, Receptors, Opioid, mu, Structure-Activity Relationship|
Multifunctional ligands with agonist bioactivities at μ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly less adverse side effects) compared to those of existing drugs and to deliver better synergistic effects than coadministration of a mixture of multiple drugs. A systematic structure-activity relationship (SAR) study has been conducted to find multifunctional ligands with desired activities at three receptors. It has been found that introduction of Dmt (2,6-dimethyl-tyrosine) at the first position and NMePhe at the fourth position (ligand 3: H-Dmt-d-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) displays binding as well as functional selectivity for MOR over DOR while maintaining efficacy, potency, and antagonist activity at the NK1R. Dmt at the first position with Phe(4-F) at the fourth position (ligand 5: H-Dmt-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) exhibits balanced binding affinities at MOR and DOR though it has higher agonist activity at DOR over MOR. This study has led to the discovery of several novel ligands including 3 and 5 with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands 3, 5, and 7 (H-Tyr-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) showed that their stability depends on modifications at the first and fourth positions (3: T1/2 > 24 h; 5: T1/2 ≈ 6 h; 7: T1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity.
|Alternate Journal||J. Med. Chem.|
|Grant List||2P01 DA 006284 / DA / NIDA NIH HHS / United States |
R01 DA 013449 / DA / NIDA NIH HHS / United States
Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.
Faculty Member Reference:
Victor Hruby, Ph.D.
Tally Largent-Milnes, PhD
Frank Porreca, PhD
Todd Vanderah, PhD