Synthesis and Biological Properties of New 2β-Alkyl- and 2β-Aryl-3-(substituted phenyl)tropane Derivatives:  Stereochemical Effect of C-3 on Affinity and Selectivity for Neuronal Dopamine and Serotonin Transporters

Abstract

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications of its structure. In the case of the substituent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In the present study, we report our results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using Ki values rather than IC50 values when making such comparisons of transporter selectivity. One of the most interesting compounds identified in the present work is a 2, 3-diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the 5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy further underscores the versatility of this particular chemical approach to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in nonracemic form.

Rearrangement of a Mesylate Tropane Intermediate in Nucleophilic Substitution Reactions. Synthesis of Aza-Bicyclo[3.2.1]octane and Aza-Bicyclo[3.2.2]nonane Ethers, Imides, and Amines

“…Derivatives 13 , 14 , and 16 − 19 were obtained by unambiguous route from natural (−)-cocaine, and their NMR data were in agreement with the configuration (1 R ,2 S ,3 S ,5 S ) of the tropane structure I . − Comparison between the established tropane structure of alcohol 4 and derivatives 13 , 14 , and 16 − 19 showed close chemical shift values in both carbon and proton NMR. In every case the chemical shifts of C 1 and C 5 were in the range 61−68 ppm, which is characteristic of bridgehead carbons in structure I .…”

“…The rearranged derivatives were prepared from alcohol intermediate 4 , whose configuration (1 R ,2 S ,3 S ,5 S ) is also known . The proposed mechanism of the rearrangement (Scheme ) predicts the absolute configuration of structure II to be (1 S ,2 R ,3 S ,5 S ), after inversion of configuration for C 1 and a change in naming group priorities for C 2 .…”

“…We therefore investigated the synthesis of 2β-alkylated tropane derivatives (ethers and amines) in greater detail, using the mesylate 5 (Scheme ) from 2β-hydroxymethyl-3β-(4-methylphenyltropane) 4 , , readily available from cocaine. Here we report that rearrangement occurred when 2β-methanesulfonyloxymethyl- N -methyltropane intermediate 5 was used in nucleophilic substitution reactions with alcohols, imides, or amines, to lead to aza-bicyclo[3.2.2]nonane derivatives 6 − 12 .…”

Natural and engineered coding variation in antidepressant-sensitive serotonin transporters

“…These data are difficult to link to physiological aspects of DA and 5-HT signaling given the significant compensatory changes that arise with the constitutive DAT and SERT KOs. Nonetheless, these findings remind us of functional interactions between 5-HT and DA systems (Carlsson et al, 2007; Navailles and De Deurwaerdere, 2010; Larsen et al, 2011), particularly given the higher affinity that SERT exhibits for cocaine as compared with DAT (Ritz et al, 1987; Kozikowski et al, 1998). …”

Structural Remodeling of Cocaine: Design and Synthesis of Trisubstituted Cyclopropanes as Selective Serotonin Reuptake Inhibitors

“…Our recent work in this area has led to the discovery of several different series of compounds with novel structures that are distinct from those of the traditional tropane analogues belonging to the Sterling–Winthrop (WIN) series 19–27 Structure–activity relationship (SAR) studies have shown that some of these newer ligands exhibit good to excellent potency and selectivity for the DAT, SERT, or NET.…”