Abstract

The abuse of methamphetamine (METH) has escalated in recent years and effective treatments to curtail its use are not yet available. Our preliminary results demonstrate that a-lobeline (LOB), a weakly basic lipophilic alkaloid, binds to the high affinity nicotinic receptor binding site (a4P2 subtype) and acts as an antagonist at the nicotinic receptor subtype which evokes dopamine (DA) release (purportedly, the a3P2 subtype). LOB also inhibits the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2), but does not inhibit monoamine oxidase (MAO). Moreover, LOB inhibits amphetamine (AMPT)-evoked DA release and METH self-administration in rats. Our preliminary results suggest that VMAT2 may be an important new therapeutic target for the treatment of METH abuse. With this in mind, we have begun synthesizing a series of LOB analogs to target VMAT2. The long-term goal of this proposal is to develop our lead LOB analog, 2R,6S-N-methyl-2,6-

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013519-03
Application #
6515800
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Appel, Nathan M
Project Start
2000-08-15
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$350,821
Indirect Cost

  Institution

Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Kangiser, Megan M; Dwoskin, Linda P; Zheng, Guangrong et al. (2018) Varenicline and GZ-793A differentially decrease methamphetamine self-administration under a multiple schedule of reinforcement in rats. Behav Pharmacol 29:87-97
Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R et al. (2017) Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2. Bioorg Med Chem Lett 27:5467-5472
Nickell, Justin R; Culver, John P; Janganati, Venumadhav et al. (2016) 1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2. Bioorg Med Chem Lett 26:2997-3000
Nickell, Justin R; Culver, John P; Janganati, Venumadhav et al. (2016) Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2. Bioorg Med Chem Lett 26:4441-4445
Zheng, Guangrong; Crooks, Peter A (2015) Synthesis of Lobeline, Lobelane and their Analogues. A Review. Org Prep Proced Int 47:317-337
Leboff, M S; Cobb, H; Gao, L Y et al. (2013) Celiac disease is not increased in women with hip fractures and low vitamin D levels. J Nutr Health Aging 17:562-5
Horton, David B; Nickell, Justin R; Zheng, Guangrong et al. (2013) GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine. J Neurochem 127:177-86
Penthala, Narsimha Reddy; Ponugoti, Purushothama Rao; Nickell, Justin R et al. (2013) Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2). Bioorg Med Chem Lett 23:3342-5
Zheng, Guangrong; Horton, David B; Penthala, Narsimha Reddy et al. (2013) Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. Medchemcomm 4:564-568
Berry, Jennifer N; Neugebauer, Nichole M; Bardo, Michael T (2012) Reinstatement of methamphetamine conditioned place preference in nicotine-sensitized rats. Behav Brain Res 235:158-65

Showing the most recent 10 out of 48 publications