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.
10.1016/j.tetlet.2014.07.043
The study presents an optimized biomimetic method for the conversion of various α-amino acids to aldehydes using sodium hypochlorite (NaOCl), which serves as an oxidizing agent for the decarboxylation of amino acids. The aldehyde products can then be transformed into tetrahydroisoquinolines, either racemic or (S)-enantiomer forms, through the Pictet–Spengler reaction with dopamine. The study utilizes a phosphate buffer to maximize regioselectivity for the racemic products and a maleic acid buffer for the enantioselective enzymatic synthesis of (S)-enantiomer products using norcoclaurine synthase. The purpose of these chemicals is to facilitate the synthesis of tetrahydroisoquinolines, which are found in numerous natural products and synthetic compounds with pharmacological activity, including benzoisoquinoline alkaloids. The study aims to synthesize novel BIAs with potential pharmacological utility by employing precursor-directed biosynthesis, avoiding the need for chromatography and ensuring the preparations are free of toxic chemical species.
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/jm801162z
The research aimed to identify potent and selective compounds for both the dopamine transporter (DAT) and serotonin transporter (5-HTT) relative to the norepinephrine transporter (NET) to potentially develop new pharmacotherapies for treating cocaine abuse. The study synthesized and evaluated a series of 3′-(substituted phenyl)tropane-2′-carboxylic acid methyl esters (7a-g), 3′-(4-methoxyphenyl)tropane-2′-carboxylic acid esters (8a-j), and 3′-(4-methoxyphenyl)-2′-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9). Key chemicals used included natural (-)-cocaine as the starting material, various Grignard reagents, bromine, iodine chloride, and different alcohols for esterification. The most potent and selective compound identified was 3′-(4-methoxyphenyl)tropane-2′-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i), with an IC50 value of 2.5 nM for the DAT and Ki values of 3.5 and 2040 nM for the 5-HTT and NET, respectively. The study concluded that mixed action inhibitors of DAT and -HT5T, such as compound 8i, warrant further investigation as potential treatments for cocaine addiction.
