10.1021/jm9506581
The research focuses on the structure-activity relationship (SAR) studies of novel 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs, with the aim of synthesizing and biologically evaluating their binding at dopamine (DA) and serotonin (5HT) transporters in rat striatal membranes. The purpose was to generate compounds with optimum activity and selectivity for the DA transporter by introducing different alkyl chain lengths and substitutions. The study concluded that unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter, with compound 9a showing the highest potency and selectivity for the DA transporter. Key chemicals used in the synthesis process included variously substituted benzhydrols, ketals, phosphonoacetates, and lithium aluminum hydride, among others, to construct the piperidine analogs with different structural modifications.
10.1016/j.bmc.2007.11.009
The study investigates the synthesis and biological activity of bivalent 2b-carbomethoxy-3b-(3,4-dichlorophenyl)8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine (DAT) and serotonin (SERT) transporters. The researchers designed bivalent compounds, where two tropane moieties are linked by an intervening chain, to explore the existence of adjacent tropane binding sites on these transporters and to compare the binding sites for different types of tropanes. The parent compounds, including 8-azatropane, 8-oxatropane, and 8-thiatropane, were synthesized and used as the basis for creating bivalent ligands with varying linker lengths. The study found that bivalent 8-azatropanes showed significantly reduced inhibitory potency at both DAT and SERT compared to their monovalent counterparts, suggesting that there are unlikely to be two tropane binding sites in close proximity on either transporter. Additionally, the results indicated that the binding sites for 8-azatropanes are different from those for 8-oxatropanes or 8-thiatropanes, as bivalent ligands containing these latter types of tropanes lost significant potency or were completely inactive at the transporters.
10.1021/jm00377a021
The study investigates the synthesis and pharmacological properties of a series of nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins. The researchers synthesized various compounds, including cis and trans aminotetralins with different substituents in the 4-aryl ring, such as chlorine, bromine, trifluoromethyl, and methoxy groups. These compounds were tested for their ability to inhibit the uptake of neurotransmitters like dopamine (DA), serotonin (5-HT), and norepinephrine (NE) in vitro. The study found that certain cis compounds, particularly those with electron-withdrawing groups in the 4-position of the 4-aryl ring, exhibited potent and selective 5-HT uptake blocking activity, which is a desirable property for antidepressant agents. The trans compounds were generally more potent inhibitors of NE uptake and also blocked DA uptake. The study also involved the resolution of racemic mixtures into their enantiomers, revealing significant differences in activity between the dextro and levo forms, with the dextro enantiomers of cis compounds being highly selective for 5-HT uptake blockade. The findings suggest that these compounds could serve as potential antidepressants with reduced side effects compared to traditional tricyclic antidepressants.
10.1021/ol071083s
The study presents a novel synthetic route to 1-oxo-5-hydroxytryptamine (1-OT), a benzofuran analogue of serotonin (5-HT), using p-benzoquinone and 2,3-dihydrofuran in a [3+2] cycloaddition followed by a Lewis acid-catalyzed isomerization. The research investigates the role of the indolic proton in serotonin's activation of the 5-HT3 receptor, revealing that 1-OT acts as a competent agonist with an EC50 value nearly identical to serotonin, indicating that the indole nitrogen's hydrogen bond is not essential for receptor activation. This finding suggests that the binding site of the 5-HT3 receptor may not require a hydrogen bond from the indole nitrogen of serotonin, and the new synthetic route allows for the production of 1-OT derivatives to further explore 5-HT receptor binding sites.
10.1021/jm00350a008
The research focuses on the synthesis and pharmacological evaluation of monophenolic octahydrobenzo[f]quinolines, aiming to investigate their potential as central dopamine and serotonin receptor agonists. The study synthesized eight different monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and tested their effects on central dopaminergic and serotonergic systems using biochemical and behavioral methods in rats. The results showed that the trans isomers were consistently more potent than their cis counterparts in stimulating both dopamine and serotonin receptors. Specifically, the trans-7-, -8-, and -9-hydroxy isomers exhibited significant dopaminergic activity, while the trans-10-hydroxy isomer displayed selective serotoninergic activity. The study concluded that the position of the hydroxy group is crucial for determining the type of biological activity (dopaminergic or serotoninergic) exhibited by these compounds.
10.1021/jm00396a014
This research aimed to synthesize and test N,N-dialkylated monophenolic derivatives of trans-2-phenylcyclopropylamine for their activity as central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor agonists. The study found that a hydroxy substituent in the 2- or 3-position of the phenyl ring was necessary for 5-HT-receptor stimulation, with N,N-diethyl or N,N-di-n-propyl substitution yielding the most potent 5-HT-receptor agonists. Notably, the 4-hydroxy and 3,4-dihydroxy derivatives were inactive at central DA and 5-HT receptors. The compounds were synthesized using various chemical reactions, including cyclopropanation, Curtius rearrangement, and reductive methylation, with starting materials such as methyl trans-cinnamates and ethyl diazoacetate.
10.1021/ol050790n
The research explores a method for synthesizing conformationally restricted homotryptamine-like compounds, which are of interest in drug discovery for their potential as selective serotonin reuptake inhibitors (SSRIs). The study focuses on the catalytic asymmetric cyclopropanation of 1-tosyl-3-vinylindoles using ethyl- and tert-butyldiazoacetate, catalyzed by pybox-Ru(II) complexes. The aim is to develop a scalable and efficient synthesis that avoids the use of diazomethane and offers greater catalytic efficiency than existing methods. The researchers found that 1-tosyl-3-vinylindoles are excellent substrates for this reaction, yielding N-protected trans-2-(indol-3-yl)-1-cyclopropanecarboxylic esters with good yields and high enantiomeric excess (81?88% ee). The study demonstrates the utility of this method by converting one of the cycloadducts into the potent SSRI BMS-505130, which showed a 10-fold improvement in binding potency to the serotonin transporter compared to a more flexible analogue. The findings suggest that this catalytic asymmetric cyclopropanation method is a valuable approach for synthesizing conformationally restricted homotryptamines with potential therapeutic applications.
10.1021/ja076403h
The research aims to propose a model for the binding of serotonin (5-HT) to the human serotonin transporter (hSERT) using molecular modeling and experimental validation. The study constructs homology models of hSERT based on the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, and performs induced fit docking of 5-HT into these models, resulting in two different binding modes. To validate the binding experimentally, the researchers measured the binding affinities of 5-HT and 17 analogues towards wild type and 13 single point mutants of hSERT using an approach called paired mutant-ligand analogue complementation (PaMLAC). The study concludes that the interactions between Asp98 and the primary amine of 5-HT and between the C6 position of 5-HT and hSERT position 173 were confirmed. The binding mode where the 5-hydroxyl group of 5-HT is in close proximity to Thr439 was biochemically supported. This research provides valuable insights into the binding mechanism of serotonin to its transporter, which is crucial for understanding the function of hSERT and has implications for the development of drugs targeting anxiety and depression.
