3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.

Cocaine addiction continues to present a global problem. Notwithstanding substantial research, a clinically useful candidate to address this addiction has yet to emerge and physicians confronted with addicted patients continue to lack appropriate medications. Nonetheless, a substantial understanding of this disease has emerged, and the directions that discovery research may take in order to uncover a useful medication have made considerable advances.Cocaine is a potent stimulant of the central nervous system. It owes its reinforcing and stimulant properties to its ability to inhibit monoamine uptake systems such as the Dopamine Transporter (DAT), and the Serotonin Transporter (SERT) located on presynaptic neurons in the nucleus accumbens and striatum.1 -8 Cocaine inhibition of these monoamine uptake systems reduces the removal of excess dopamine from the synapse. The resultant increase in synaptic dopamine concentration increases activation of postsynaptic dopamine receptors. This hyperstimulation of postsynaptic receptors is responsible for cocaine's stimulant activity. The reinforcing and addictive properties of cocaine are postulated to be related to its pharmacokinetic profile9 characterized by its immediate effect (<15 seconds) and short duration of action (10-15 minutes). Therefore, the search for replacement therapeutic agents has focused on the design of compounds that bind selectively to the DAT, but manifest slow onset of stimulatory action with long duration of action.9 © 2010 Elsevier Ltd. All rights reserved. * Mail correspondence to: Dr. Peter Meltzer, Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA, Telephone (781) 932-4142, Fax (781) 933-6695, Meltzer@organixinc.com, URL: http://www.organixinc.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary InformationSupplementary information associated with this article can be found, in the online version, as doi: . Synthetic procedures, spectral data, and biological assays are provided. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2012 January 1. We now report the synthesis and biological evaluation of a series of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes and oct-2-enes. These compounds have proved potent and selective inhibitors of DAT.The synthesis of this new class of 2-isoxazolyl-3-aryl-8-thiabicyclo[3.2.1]oct-2-enes 4 and -2-anes, 5 and 6, is presented in Scheme 1. The starting unsaturated C2-methyl esters 1 provided the isoxazoles 4 as described below. These esters 1 were then reduced with samarium io...