131206-60-5Relevant academic research and scientific papers
Binding mode selection determines the action of ecstasy homologs at monoamine transporters
Sandtner, Walter,Stockner, Thomas,Hasenhuetl, Peter S.,Partilla, John S.,Seddik, Amir,Zhang, Yuan-Wei,Cao, Jianjing,Holy, Marion,Steinkellner, Thomas,Rudnick, Gary,Baumann, Michael H.,Ecker, Gerhard F.,Newman, Amy Hauck,Sitte, Harald H.
, p. 165 - 175 (2016)
Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-Trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective proteinligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-Affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a lowaffinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-Affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.
Research on the central activity and analgesia of N-substituted analogs of the amphetamine derivative 3,4-methylenedioxyphenylisopropylamine
Braun,Shulgin,Braun
, p. 825 - 830 (2007/10/02)
N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (MDA) were tested ror analgesic potency and influence on motor activity in mice following potency and influence on motor activity in mice following oral administration. These compounds also were tested for thei psychotomimetic potency in man. Unsubstituted MDA and its monoalkyl-homologs with a low number of C-atoms (N-methyl-, N-methyl-, N-ethyl-MDA) showed both enhancement of motor-activity in mice and psychotomimetic effects in man. MDA and N-methyl-MDA also showed an analgesic effec wthich was enhanced by the inclusion of a weakly labis group (N-mallyl, N-hydroxyethyl). These latter two compounds, however, did not influence motor-activity, which makes them more recommendable as possible analgesic compounds. Structural parallels between these compounds, morphine, endorphins and enkephalins, may explain their similar spectrum of pharmacological effects.
Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine)
Braun,Shulgin,Braun
, p. 192 - 195 (2007/10/02)
The known central nervous system activity of 3,4-methylenedioxyphenylisopropylamine and its N-methyl homolog prompted the synthesis of a series of analogs with substituents on the nitrogen atom. Most of these analogs (R = alkyl, alkenyl, hydroxy, alkoxy, and alkoxyalkyl) were prepared by the reductive alkylation of 3,4-methylenedioxyphenylacetone with the appropriate amine and sodium cyanoborohydride. Hindered isomers were synthesized indirectly. Measurements of their pharmacological activity in several animal assays and in human subjects indicated that the central activity decreased with the increasing bulk of the N-substituent.
