Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives

Abstract

3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT. These SAR studies provide further evidence for the varied binding requirements of structurally diverse tropane-based ligands and support future studies to elucidate DAT binding requirements in relation to cocaine-like behavioral endpoints.

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…The K i values determined with the 3b-aryltropanes with 2b-substitutions at the DAT ranged from 18.9 for LX-10 to 68.0 nM for LX-19 (Table 3). These values represent affinities as much as 3-fold higher than those reported previously (Xu et al, 2004) owing to the use of a sucrose-phosphate rather than a HEPES buffer (unpublished observations). Additionally, the 2b-substituted analogs had affinities that were from 10-to 25-fold greater than the respective analogs with a-substitutions.…”

“…As the diphenylether moiety of the BZT analogs was shown to be critical for their deviation from typical cocaine-like activity, aryltropane analogs with diphenylether substituents at the C-2 position were of interest. Xu et al (2004) predicted and confirmed that BZT analogs with C-2 substitutions have less affinity for M 1 receptors than the unsubstituted compounds, but retain activity at DAT. In the present study, we report atypical behavioral effects of a series of 2-substituted 3b-aryltropane cocaine analogs (Xu et al, 2004) and explored potential mechanism for their atypical effects.…”

“…Additionally, the 2b-substituted analogs had affinities that were from 10-to 25-fold greater than the respective analogs with a-substitutions. In contrast to the b-substituted analogs, the a-substituted analogs were generally not selective for DAT over serotonin transporter (SERT), on the basis of previously published affinities for the SERT (Xu et al, 2004). None of the compounds had better than micromolar affinity for either s 1 R or s 2 R binding sites, and those affinities were not appreciably different among the enantiomers (Table 3).…”

“…Drugs. (-)-Cocaine HCl was purchased from MilliporeSigma (St. Louis, MO), and analogs of phenyltropane were synthesized at the University of New Orleans (Xu et al, 2004). Figure 1 shows reference compounds and structures of 2-substituted 3b-aryltropane compounds used in this study.…”

“…1) decrease affinity for the M 1 muscarinic receptor. Additionally, analogs of cocaine exhibit a high degree of tolerance for C-2 substitutions of the tropane ring, as substituents with considerable steric bulk typically do not interfere with cocaine-like pharmacological activity (Carroll et al, 1992;Xu et al, 2004). As the diphenylether moiety of the BZT analogs was shown to be critical for their deviation from typical cocaine-like activity, aryltropane analogs with diphenylether substituents at the C-2 position were of interest.…”