The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters

Abstract

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.

Synthesis and Biological Evaluation of Bivalent Ligands for the Cannabinoid 1 Receptor

“…Ideally, bivalent ligands with linkers of optimal length will bind to receptor dimers with greatly enhanced affinity due to the formation of thermodynamically stable complexes. Indeed, significant progress has been made in a number of GPCRs including opioids, 13, 15 adrenergic, 16, 17 dopamine, 18 serotonin 19, 20 and muscarinic receptors. 21, 22 Most significantly, much success has been recently achieved by Portoghese and co-workers with bivalent opioid ligands in vivo .…”

Monoamine Transporters

“…It is currently believed that the rational design and development of high-affinity, long acting DAT ligands with specific pharmacokinetic/dynamic properties might lead to the discovery of optimal medications for stimulant addiction (55, 56). A variety of molecules based on the 3-aryltropanes (WIN compounds) (57), the 1,4-dialkylpiperazines (e.g., GBR 12909 and its analogues) (55), and analogues of benztropine (BZT) (56) have all been synthesized, tested in vitro for binding at different transporters and receptors, and evaluated in preclinical models. Of these, BZT analogs exhibit ideal characteristics in preclinical assays, blocking the behavioral effects of cocaine and AMPH and exhibiting weak abuse liability in place preference and self-administration assays (58-60).…”

Catalytic Asymmetric Synthesis of 8‐Oxabicyclooctanes by Intermolecular [5+2] Pyrylium Cycloadditions

“…Chiral 8-oxabicyclo[3.2.1]octane architectures reside at the core of numerous natural products and biologically significant compounds (Scheme 1). [1,2] Heterocycles of this class have also proven to be valuable intermediates in the stereoselective synthesis of oxygenated seven-membered carbocycles [3] and tetrahydrofuran derivatives. [4] Successful stereoselective approaches to the 8-oxabicyclo[3.2.1]octane framework have relied on transition-metal-catalyzed [3+2] cycloadditions, [5] [4+3] cycloadditions, [6] diastereoselective [5+2] cycloadditions, [7] and diastereoselective cascade cyclizations.…”