The objectives of the proposed research are to develop improved molecular probes for specific cocaine recognition sites in primate brain and to provide fundamental information on the distribution and pharmacological properties of these sites in relation to cocaine abuse. The relatively low affinity and rapid dissociation of [3H]cocaine limited its suitability for these studies and a higher affinity cocaine congener [3H]CFT ([3H]WIN 35,428), which binds to virtually the same sites as [3H]cocaine, was developed. (3H]CFT was suitable for mapping high density cocaine recognition sites in brain, for monitoring dopamine nerve terminal degeneration in Parkinson's diseased brain and as a PET (positron emission tomography) imaging ligand. We propose to continue our ongoing studies with [3H]CFT to clarify the functional relevance of high- and low-affinity binding components for cocaine and to characterize cocaine binding sites in discrete brain regions revealed by autoradiographic mapping of [3H]CFT binding. Although [3H]CFT is an effective probe for cocaine recognition sites, its moderate affinity for the dopamine transporter, a principle target of cocaine in the brain, has prompted a search for higher affinity ligands. We will evaluate the higher affinity ligands [125I]RTI-55 and [3H]Lu 19-005, using techniques similar to those used in our initial studies with [3H]CFT. In addition, novel phenyltropane analogs (3-iodo, 4-chloro, 3,4-dichloro) will be synthesized or acquired, and evaluated in coordinated biochemical and behavioral studies. The relative potencies of these compounds for inhibiting [3H]CFT (dopamine transporter) and [3H]citalopram (serotonin transporter) binding, for producing cocaine-like discriminative stimulus effects and for maintaining i.v. self-administration will be measured. The results will be compared with data from RTI-55 and Lu 19-005. Based on our findings, we will select the highest affinity and most selective for the dopamine transporter for further development. The proposed research will provide needed information for defining the principal neurochemical targets of cocaine in the brain and for developing rational approaches to the pharmacological management of cocaine abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Program Officer
Kline, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Veterinary Sciences
Schools of Medicine
United States
Zip Code
Torun, Lokman; Madras, Bertha K; Meltzer, Peter C (2012) Synthesis and structure-activity relationship studies of 3-biaryl-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters. Bioorg Med Chem 20:2762-72
Purushotham, Madhusudhan; Sheri, Anjaneyulu; Pham-Huu, Duy-Phong et al. (2011) The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes. Bioorg Med Chem Lett 21:48-51
Vallender, Eric J; Lynch, Laurie; Novak, Melinda A et al. (2009) Polymorphisms in the 3' UTR of the serotonin transporter are associated with cognitive flexibility in rhesus macaques. Am J Med Genet B Neuropsychiatr Genet 150B:467-75
Vallender, E J; Priddy, C M; Hakim, S et al. (2008) Functional variation in the 3'untranslated region of the serotonin transporter in human and rhesus macaque. Genes Brain Behav 7:690-7
Chen, Guo-Lin; Vallender, Eric J; Miller, Gregory M (2008) Functional characterization of the human TPH2 5'regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum Genet 122:645-57
Xie, Zhihua; Miller, Gregory M (2008) Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther 325:617-28
Xie, Zhihua; Vallender, Eric J; Yu, Naichen et al. (2008) Cloning, expression, and functional analysis of rhesus monkey trace amine-associated receptor 6: evidence for lack of monoaminergic association. J Neurosci Res 86:3435-46
Verrico, Christopher D; Lynch, Laurie; Fahey, Michele A et al. (2008) MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor. J Psychopharmacol 22:187-202
Vallender, Eric J; Priddy, Cassandra M; Chen, Guo-Lin et al. (2008) Human expression variation in the mu-opioid receptor is paralleled in rhesus macaque. Behav Genet 38:390-5
Xie, Zhihua; Westmoreland, Susan V; Miller, Gregory M (2008) Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes. J Pharmacol Exp Ther 325:629-40

Showing the most recent 10 out of 73 publications