Cocaine dependence is a problem of national significance. In the past decade there has been a considerable advance in the understanding of the chemistry and pharmacology of cocaine dependence. Notwithstanding, no cocaine pharmacotherapy has yet been approved by the FDA. A number of lead compounds are undergoing pharmacological evaluation as potential therapeutic agents. Cocaine's reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters. The goal of this project is to design potential pharmacotherapies for cocaine dependence. We will focus on the development of an understanding of the interaction between ligand and monoamine neurotransmitter uptake systems. We propose to expand our search for compounds that bind to DAT and SERT mechanisms but disturb dopamine (DA) uptake minimally, for compounds with slow onset and long duration of action, and for mechanism-based inhibitors of cocaine binding. We will focus on three classes: 8-oxabicyclo[3,2,1]octanes (oxatropanes), 8-azabicyclo[3,2,1]octanes (tropanes) and pyrovalerone analogues.
The Specific Aims are: Synthesis and evaluation of (i) non-nitrogen tropane analogs, (ii) 6- and 7 hydroxylated 8-azatropane prodrugs, (iii) 6- and 7-hydroxylated 8-oxatropan(en)es, (iv) dopamine sparing cocaine antagonists that bind irreversibly to the cocaine site, (v) 3-heterobiaryltropanes. (vi) analogues of pyrovalerone.
|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|
|Meltzer, Peter C; Kryatova, Olga; Pham-Huu, Duy-Phong et al. (2008) The synthesis of bivalent 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters. Bioorg Med Chem 16:1832-41|
|Pham-Huu, Duy-Phong; Deschamps, Jeffrey R; Liu, Shanghao et al. (2007) Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. Bioorg Med Chem 15:1067-82|
|Meltzer, Peter C; Butler, David; Deschamps, Jeffrey R et al. (2006) 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 49:1420-32|
|Meltzer, Peter C; McPhee, Mark; Madras, Bertha K (2003) Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes. Bioorg Med Chem Lett 13:4133-7|
|Meltzer, Peter C; Wang, Pinglang; Blundell, Paul et al. (2003) Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate. J Med Chem 46:1538-45|
|Madras, Bertha K; Fahey, Michele A; Miller, Gregory M et al. (2003) Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Eur J Pharmacol 479:41-51|
|Meltzer, Peter C; Liu, Shanghao; Blanchette, Heather et al. (2002) Design and synthesis of an irreversible dopamine-sparing cocaine antagonist. Bioorg Med Chem 10:3583-91|
|Meltzer, P C; Wang, B; Chen, Z et al. (2001) Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. J Med Chem 44:2619-35|
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