Cocaine abuse and toxicities are serious threats to human health in the United States and the World. To date, there are no effective treatments for the abuse or toxicities associated with cocaine use. Agents targeting the sites of action of cocaine, such as the dopamine transporter, have met with limited success. Recently, it has been noted that sigma receptor antagonists can attenuate and block the toxic and the stimulant/rewarding effects of cocaine. Thus, the sigma receptor is a valid target for medication development for the treatment of cocaine toxicities and addiction. Sigma receptors exist as two distinct subtypes, sigma-1 and sigma-2. To date, only the sigma-1 receptor has been cloned. Sigma-1 receptors have been shown to be involved in the toxic and addictive effects of cocaine and are a logical target for the development of novel therapeutics. Although the involvement of sigma-2 receptors is not well-established, their involvement cannot be completely ruled out. This knowledge has been hampered by the availability of selective sigma-2 agents. However, existing data is highly suggestive of their involvement in the stimulant and toxic effects of cocaine. We therefore hypothesize that targeting sigma-1 and sigma-2 receptors, either in combination or through subtype-selective agents, can provide effective medications for treatment of cocaine toxicities and addiction. To date we have generated over thirty, structurally-related compounds based on a rational design (from known sigma antagonists) that have demonstrated high affinity for sigma-1 and sigma-2 receptors. In addition, some of these compounds have been evaluated in vivo and prevented cocaine-induced convulsions and locomotor activity. To test our hypothesis, the specific aims of the project are: 1) To develop, in a parallel synthesis fashion, novel sigma-1 and sigma-2 ligands with either selectivity for sigma-1, sigma-2, or a combination of affinities at each receptor. 2) To demonstrate these compounds like the preliminary examples have high affinity for sigma receptors and lack activity for other receptor types. 3) To develop three-dimensional pharmacophore models, based on our ligands that will help define the ligands selectivity profile and mode of binding at the receptor and promote father design of novel ligands. 4) To demonstrate the novel compounds attenuate cocaine-induced behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023205-04
Application #
7799912
Study Section
Special Emphasis Panel (ZDA1-RXL-E (11))
Program Officer
Shih, Ming L
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$345,584
Indirect Cost
Name
University of Mississippi
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
067713560
City
University
State
MS
Country
United States
Zip Code
38677
Hong, Weimin Conrad; Yano, Hideaki; Hiranita, Takato et al. (2017) The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats. J Biol Chem 292:11250-11261
Liu, Xinying; Fu, Yingmei; Yang, Huan et al. (2017) Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel. Oncotarget 8:59345-59358
Katz, Jonathan L; Hiranita, Takato; Kopajtic, Theresa A et al. (2016) Blockade of Cocaine or ? Receptor Agonist Self Administration by Subtype-Selective ? Receptor Antagonists. J Pharmacol Exp Ther 358:109-24
Nicholson, Hilary; Mesangeau, Christophe; McCurdy, Christopher R et al. (2016) Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma. J Pharmacol Exp Ther 356:232-43
Chu, Uyen B; Mavlyutov, Timur A; Chu, Ming-Liang et al. (2015) The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 are Different Binding Sites Derived From Independent Genes. EBioMedicine 2:1806-13
Nicholson, Hilary; Comeau, Anthony; Mesangeau, Christophe et al. (2015) Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity. J Pharmacol Exp Ther 354:203-12
Robson, Matthew J; Turner, Ryan C; Naser, Zachary J et al. (2014) SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation. Exp Neurol 254:180-9
James, Michelle L; Shen, Bin; Nielsen, Carsten H et al. (2014) Evaluation of ?-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. J Nucl Med 55:147-53
Kaushal, Nidhi; Robson, Matthew J; Rosen, Abagail et al. (2014) Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro. Eur J Pharmacol 724:193-203
Nguyen, Linda; Kaushal, Nidhi; Robson, Matthew J et al. (2014) Sigma receptors as potential therapeutic targets for neuroprotection. Eur J Pharmacol 743:42-7

Showing the most recent 10 out of 32 publications