This proposal represents an application for a Research Career Award (K02) focused on the candidate's long-term goal of developing agents, which attenuate the toxic effects of drugs of abuse. The approach to achieving this goal is to have a research program that seeks to solve problems associated with drug abuse and dependence through testing hypotheses with chemistry-based approaches. The proposed research plan comprises of three projects, sharing the common theme of developing agents to attenuate the potentially lethal effects of drugs of abuse. In the case of opioids, the goal is to develop morphine-like analgesics which do not give rise to the severe constipation seen with current agents; for cocaine, the goal is to develop sigma receptor-based agents as potential treatments for cocaine overdose; for GHB, the goal is to develop a treatment for GHB overdose based on a mixed profile of GHB and GABA-B antagonism. My short-term approach to the latter two goals is to develop the current collaborations with Drs. France and Matsumoto to a point where I am able to take the lead as PI on new R01 submissions. My plans for the opioids is to develop a new research program based on pharmacokinetic mechanisms of tolerance, and initially submit an R21 application to gain valuable preliminary data. This approach is based on the hypothesis that as tolerance is reduced, the ever-increasing doses of morphine (which leads to the constipation) will not be required. My long-tern career goal is to develop these projects and my collaborations to the point where I am able to translate these medications into the clinic or emergency room. The candidate will spend 75% of his time on NIH-funded research. This award will allow the candidate to be relieved from many teaching and administrative responsibilities, thereby allowing him to focus on current and future research projects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA019634-03
Application #
7221968
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Shih, Ming L
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$105,377
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
Shim, Jihyun; Coop, Andrew; MacKerell Jr, Alexander D (2013) Molecular details of the activation of the ? opioid receptor. J Phys Chem B 117:7907-17
Stavitskaya, Lidiya; Seminerio, Michael J; Healy, Jason R et al. (2013) Effect of ring-constrained phenylpropyloxyethylamines on sigma receptors. Bioorg Med Chem 21:4923-7
Robson, Matthew J; Seminerio, Michael J; McCurdy, Christopher R et al. (2013) ? Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation. Pharmacol Rep 65:343-9
Shim, Jihyun; Coop, Andrew; MacKerell Jr, Alexander D (2011) Consensus 3D model of ?-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
Seminerio, Michael J; Kaushal, Nidhi; Shaikh, Jamaluddin et al. (2011) Sigma (ýý) receptor ligand, AC927 (N-phenethylpiperidine oxalate), attenuates methamphetamine-induced hyperthermia and serotonin damage in mice. Pharmacol Biochem Behav 98:12-20
Shim, Jihyun; Mackerell Jr, Alexander D (2011) Computational ligand-based rational design: Role of conformational sampling and force fields in model development. Medchemcomm 2:356-370
Matsumoto, Rae R; Li, Su-Min; Katz, Jonathan L et al. (2011) Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine. Drug Alcohol Depend 118:40-7
Cunningham, Christopher W; Hom, Kellie; Acharya, Chayan et al. (2010) Synthesis and Characterization of a Novel Diels - Alder Adduct of Codeine. Helv Chim Acta 93:220-226
Stavitskaya, Lidiya; Seminerio, Michael J; Matthews-Tsourounis, Marilyn M et al. (2010) The effect of the pyridyl nitrogen position in pyridylpiperazine sigma ligands. Bioorg Med Chem Lett 20:2564-5

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