Chronic clinical pain remains poorly treated. The use of mu opioid analgesics such as morphine can treat the pain, but the severe undesired effects of morphine and other mu agonists limit their use. Indeed, the rapid development of tolerance causes ever increasing doses to be administered, increasing the severity of the undesired effects. Studies have shown the coadministration of a delta opioid antagonist, together with morphine causes a slower build-up of tolerance than administration of morphine alone. Further, the use of a peptide with a dual profile of mu agonism/delta antagonism has been reported to give rise to little tolerance. Thus, the aim of this continuing research project is to develop potent non-peptide mu agonists, which also possess a profile of delta antagonism. The orvinols (e.g. etorphine) are a class of potent mu opioid agonists, that also interact with kappa and delta receptors, generally displaying delta agonism. Our hypothesis is that the delta efficacy of the orvinols can be reduced by the introduction of an aromatic group in a position that corresponds to the position of the indole in the indolomorphinans (e.g. naltrindole) or the benzylidene in the opioid benzylidenes (e.g. benzylidenenaltrexone (BNTX)), two important classes of low efficacy delta opioid ligands. By reducing delta efficacy and retaining high mu efficacy, analogs of the orvinols with the desired profile will result. The approach to be used consists of the development of a pharmacophore model of delta efficacy using a novel molecular modeling approach, and the design of target molecules with a suitably positioned aromatic ring. Included are 5,14-bridged and 6,14-bridged-morphinan based orvinols selected by the model. Novel chemical methodology will be developed and applied to the synthesis of 6,14-bridged-4,5-epoxymorphinan targets, analogs very closely related to the orvinols. The ultimate goal of this proposal is to develop potent mu opioid analgesics, to which tolerance develops slowly, or not at all, in order to reduce the undesired effects seen in the chronic treatment of clinical pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013583-09
Application #
8013890
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Hillery, Paul
Project Start
2001-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$294,972
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Metcalf, Matthew D; Rosicky, Andrew D; Hassan, Hazem E et al. (2014) Opioids and efflux transporters. Part 4: influence of N-substitution on P-glycoprotein substrate activity of noroxymorphone analogues. Bioorg Med Chem Lett 24:3592-5
Nguyen, Linda; Robson, Matthew J; Healy, Jason R et al. (2014) Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One 9:e89985
Shim, Jihyun; Coop, Andrew; MacKerell Jr, Alexander D (2013) Molecular details of the activation of the μ opioid receptor. J Phys Chem B 117:7907-17
Shim, Jihyun; Zhu, Xiao; Best, Robert B et al. (2013) (Ala)(4)-X-(Ala)4 as a model system for the optimization of the χ1 and χ2 amino acid side-chain dihedral empirical force field parameters. J Comput Chem 34:593-603
Motel, William C; Coop, Andrew; Cunningham, Christopher W (2013) Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Mini Rev Med Chem 13:456-66
Healy, Jason R; Bezawada, Padmavani; Shim, Jihyun et al. (2013) Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities. ACS Chem Neurosci 4:1256-66
Motel, William C; Healy, Jason R; Viard, Eddy et al. (2013) Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands. Bioorg Med Chem Lett 23:6920-2
Stavitskaya, Lidiya; Shim, Jihyun; Healy, Jason R et al. (2012) Deconstructing 14-phenylpropyloxymetopon: minimal requirements for binding to mu opioid receptors. Bioorg Med Chem 20:4556-63
Shim, Jihyun; Coop, Andrew; MacKerell Jr, Alexander D (2011) Consensus 3D model of μ-opioid receptor ligand efficacy based on a quantitative Conformationally Sampled Pharmacophore. J Phys Chem B 115:7487-96
Acharya, Chayan; Coop, Andrew; Polli, James E et al. (2011) Recent advances in ligand-based drug design: relevance and utility of the conformationally sampled pharmacophore approach. Curr Comput Aided Drug Des 7:10-22

Showing the most recent 10 out of 31 publications