title: Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.
abstract: 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.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Arizona , 1306 E. University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Aswini Kumar
authors.initials: AK
authors.lastname: Giri
authors.affiliation: Departments of Chemistry and Biochemistry, University of Arizona , 1306 E. University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Apostol
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Forte
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Molnar
authors.forename: Keith M
authors.initials: KM
authors.lastname: Olson
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology, University of Arizona , 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.affiliation: Departments of Chemistry and Biochemistry, University of Arizona , 1306 E. University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D018040:Receptors, Neurokinin-1; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu