The rational design of opioid drugs requires a detailed understanding of the precise interactions between opioid ligand and opioid receptor that underlie ligand selectivity for a particular opioid receptor and that distinguish agonist from antagonist function. During the current grant period our efforts to gain that understanding have focused on the refinement and validation of models of ligand/receptor complexes for the mu and delta opioid receptors (MOR and DOR) and elucidation of the precise features of ligand-receptor interaction that differentiate binding to MOR and DOR. In the next grant period, we propose to extend these studies by applying the insights gained from initial cyclic KOR (kappa opioid receptor) peptide ligands that display high affinity but are nonselective, and from our ligand-receptor interaction models for MOR, DOR, and KOR to design new KOR ligands within the same series that achieve KOR selectivity through KOR-specific receptor interactions. We will also begin a similar process of structure based ligand design for the orphan receptor, ORL1, using a cyclic pentapeptide scaffold. If successful, these studies would represent the considerable achievement of structure-based design of structurally related selective ligands for all 4 classes of opioid receptors, two of which (KOR and ORL1) typically bind only larger peptide ligands. Further, we will follow-up exciting initial results that point to features that determine efficacy. Success in these studies would be a clear indicator of the accuracy of the ligand/receptor interaction models and the applicability of our approaches to a wide array of GPCRs. Finally, we will continue our efforts aimed at transferring peptide-derived pharmacophore information to peptidomimetic scaffolds that hold much greater potential as possible CNS active clinical agents.
The interaction of opioid drugs with their protein targets initiates the desirable and undesirable effects of these drugs. Gaining a precise understanding of these interactions is the first step toward the design and development of opioid drugs with more tailored actions, especially opioids with reduced tolerance, dependence liability, and abuse potential.
|Anand, Jessica P; Kochan, Kelsey E; Nastase, Anthony F et al. (2018) In vivo effects of ?-opioid receptor agonist/?-opioid receptor antagonist peptidomimetics following acute and repeated administration. Br J Pharmacol 175:2013-2027|
|Anand, Jessica P; Boyer, Brett T; Mosberg, Henry I et al. (2016) The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice. Psychopharmacology (Berl) 233:2479-87|
|Harland, Aubrie A; Bender, Aaron M; Griggs, Nicholas W et al. (2016) Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy ?-Opioid Receptor (MOR)/?-Opioid Receptor (DOR) Ligands. J Med Chem 59:4985-98|
|Bender, Aaron M; Griggs, Nicholas W; Anand, Jessica P et al. (2015) Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy ? opioid receptor/? opioid receptor ligands. ACS Chem Neurosci 6:1428-35|
|Geng, Jie; Pogozheva, Irina D; Mosberg, Henry I et al. (2015) Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes. J Immunol 195:3436-48|
|Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W et al. (2015) Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy ?-Opioid Receptor (MOR) Agonists/?-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities. J Med Chem 58:8952-69|
|Anand, Jessica P; Porter-Barrus, Vanessa R; Waldschmidt, Helen V et al. (2014) Translation of structure-activity relationships from cyclic mixed efficacy opioid peptides to linear analogues. Biopolymers 102:107-14|
|Mosberg, Henry I; Yeomans, Larisa; Anand, Jessica P et al. (2014) Development of a bioavailable ? opioid receptor (MOPr) agonist, ? opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance. J Med Chem 57:3148-53|
|Bender, Aaron M; Clark, Mary J; Agius, Michael P et al. (2014) Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity ? opioid receptor (MOR) agonist/? opioid receptor (DOR) antagonist ligands. Bioorg Med Chem Lett 24:548-51|
|Pogozheva, Irina D; Mosberg, Henry I; Lomize, Andrei L (2014) Life at the border: adaptation of proteins to anisotropic membrane environment. Protein Sci 23:1165-96|
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