Transporter Binding Affinity Research Articles

Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.

Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1'-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

Impact of serotonin transporter (SERT) binding affinity on the risk of libido disorders related to antidepressants

IntroductionSexual dysfunction is a frequent adverse drug reaction (ADR) of antidepressants that considerably affects quality of life and adherence to therapy. We previously investigated the potential underlying neurofunctional mechanisms by neuroimaging methods and revealed a dampening of the dopaminergic mesolimbic-mesocortical reward system along with decreased sexual functioning under serotonergic antidepressants compared to placebo.ObjectivesWithin a combined pharmacoepidemiologic and pharmacodynamic approach, we examined the association between serotonin transporter (SERT) affinity of various antidepressants and corresponding alterations in sexual desire as ADR.MethodsUsing disproportionality analyses, reporting odds ratios (RORs) were calculated for reports indicating decreased sexual desire as ADR under the antidepressants. The data were extracted from the WHO global database of individual case safety reports VigiBase and several MedDRA terms were grouped for “Sexual Desire Disorders”. For the pharmacodynamic assessment, we calculated Pearson correlation coefficients between SERT affinity and corresponding RORsResults16 signals were detected for “Sexual Desire Disorders”. We observed a statistically significant (r (20) =. 65, p = 0.001) association between SERT affinity and decreased sexual desire. Higher SERT affinity was associated with higher risk of sexual desire.ConclusionsWhile sexual dysfunctions under serotonergic medication were previously described, we now elaborated that in particular attenuated sexual desire as ADR is associated with SERT affinity of the antidepressant. These results strengthen our previously described neurofunctional model regarding sexual dysfunction under antidepressant medication and indicate that the specific SERT affinity of the antidepressant drug should be considered in clinical practice to minimize the risk of this ADR.DisclosureNo significant relationships.

The Impact of Serotonin Transporter Binding Affinity on the Risk of Bleeding Related to Antidepressants.

The alleged primary mechanism underlying bleeding events associated with antidepressants is inhibition of serotonin uptake in platelets resulting in reduced platelet aggregability and activity, and prolonged bleeding time. There is some evidence that a substance's degree of serotonin reuptake inhibition in terms of its binding affinity to the serotonin transporter (SERT) affects the magnitude of bleeding risk increase. To test this hypothesis, we performed data mining in the worldwide largest pharmacovigilance database (VigiBase) and conducted pharmacodynamically informed quantitative signal detection. Reporting odds ratios related to the standardized Medical Dictionary of Regulatory Activities query term "haemorrhages" and 24 antidepressants were calculated, and SERT binding affinities (pKi) were obtained and correlated (Pearson correlation). A strong and statistically significant correlation between substance-related reporting odds ratios and SERT binding affinities was found (r = 0.63; 95% confidence interval, 0.30-0.82; P = 0.00097). Our findings strengthen the hypothesis that inhibition of serotonin uptake contributes to the antidepressant-related bleeding risk and suggest an association between the degree of the SERT binding affinity and the bleeding risk. This supports the preferential use of antidepressants with low or no SERT binding affinity in depressed patients at risk of bleeding.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs.

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Pharmacological characterization of the aminorex analogs 4-MAR, 4,4′-DMAR, and 3,4-DMAR

4,4′-Dimethylaminorex (4,4′-DMAR) is a novel psychoactive substance (NPS) that appeared on the illicit drug market in addition to the psychostimulant 4-methylaminorex (4-MAR). Both substances are methylated derivatives of aminorex, an amphetamine-like anorectic used in the 1960ies and withdrawn from the marked due to severe cardiovascular toxicity. The aim of the present study was to characterize the in vitro pharmacological profiles of 4-MAR, 4,4′-DMAR, and 3,4-dimethylaminorex (3,4-DMAR, direx). We assessed norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney (HEK) 293 cells. We also assessed monoamine receptor and transporter binding affinities. 4,4′-DMAR potently inhibited all monoamine transporters (IC50<1 μM) with greater potency than 3,4-methlyenedioxymethamphetaime (MDMA) and displayed a higher serotonergic over dopaminergic preference, relatively similar to MDMA (DA transporter / 5-HT transporter inhibition ratio of 0.4 and 0.08 for 4,4′-DMAR and MDMA, respectively). In contrast, 4-MAR preferentially inhibited the NE and DA transporter, exhibiting a pharmacological profile more similar to amphetamine. Both 4-MAR and 4,4′-DMAR were also substrate releasers at the DAT. 3,4-DMAR only weakly inhibited the NE transporter and showed no relevant activity at the DA and 5-HT transporter. Binding affinities of all three aminorex derivatives at various monoamine receptors were negligible (Ki values >2 μM). The in vitro pharmacological profiles indicate that 4,4′-DMAR has comparable psychoactive properties and serotonergic toxicity to MDMA and may be more potent. 4-MAR is a psychostimulant similar to amphetamine or methamphetamine. 3,4-DMAR likely has only weak psychostimulant properties.

Pharmacological profile of methylphenidate-based designer drugs

BackgroundMethylphenidate-based designer drugs are new psychoactive substances (NPS) that are used outside medical settings and their pharmacology is largely unexplored. The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro. MethodsWe determined the potencies of the methylphenidate-based NPS N-benzylethylphenidate, 3,4-dichloroethylphenidate, 3,4-dichloromethylphenidate, ethylnaphthidate, ethylphenidate, 4-fluoromethylphenidate, isopropylphenidate, 4-methylmethylphenidate, methylmorphenate, and propylphenidate and the potencies of the related compounds cocaine and modafinil with respect to norepinephrine, dopamine, and serotonin transporter inhibition in transporter-transfected human embryonic kidney 293 cells. We also investigated monoamine efflux and monoamine receptor and transporter binding affinities. Furthermore, we assessed the cell integrity under assay conditions. ResultsAll methylphenidate-based substances inhibited the norepinephrine and dopamine transporters 4 to >1000-fold more potently than the serotonin transporter. Similar to methylphenidate and cocaine, methylphenidate-based NPS did not elicit transporter-mediated efflux of monoamines. Besides binding to monoamine transporters, several test drugs had affinity for adrenergic, serotonergic, and rat trace amine-associated receptors but not for dopaminergic or mouse trace amine-associated receptors. No cytotoxicity was observed after drug treatment at assay concentrations. ConclusionMethylphenidate-based substances had pharmacological profiles similar to methylphenidate and cocaine. The predominant actions on dopamine transporters vs. serotonin transporters may be relevant when considering abuse liability.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Pharmacological profile of mephedrone analogs and related new psychoactive substances

BackgroundMephedrone is a synthetic cathinone and one of the most popular recreationally used new psychoactive substances. The aim of the present study was to characterize the in vitro pharmacology of novel analogs of mephedrone and related newly emerged designer stimulants. MethodsWe determined norepinephrine, dopamine, and serotonin transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney 293 cells. We also assessed monoamine receptor and transporter binding affinities. ResultsMephedrone analogs potently inhibited the norepinephrine transporter and, with the exception of 3-methylmethcathinone (3-MMC), inhibited the serotonin transporter more potently than the dopamine transporter. Similar to classic amphetamines, mephedrone analogs were substrate-type monoamine releasers. 5-(2-Aminopropyl)indole (5-IT) was a highly potent monoamine transporter inhibitor and a releaser of dopamine and serotonin. 4-Methylamphetamine (4-MA) mediated efflux of all three monoamines and inhibited the serotonin transporter more potently than the dopamine transporter, unlike amphetamine. N-methyl-2-aminoindane (N-methyl-2-AI) was a selective norepinephrine transporter inhibitor and norepinephrine releaser, whereas 5-methoxy-6-methyl-2-aminoindane (MMAI) was a selective serotonin transporter inhibitor and serotonin releaser. All of the drugs interacted with monoamine receptors. ConclusionThe predominant actions on serotonin vs. dopamine transporters suggest that dimethylmethcathinones, 4-MA, and MMAI cause entactogenic effects similar to 3,4-methylenedioxymethamphetamine, whereas 3-MMC, 5-IT, and N-methyl-2-AI have more stimulant-type properties like amphetamine. Because of pharmacological and structural similarity to mephedrone, similar health risks can be expected for these analogs.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation

The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

Candidate Molecule for Premature Ejaculation, DA-8031: In Vivo and In Vitro Characterization of DA-8031

To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 μM for norepinephrine, and 136.9 μM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.

Quantitative structure–activity relationship studies of threo-methylphenidate analogs

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure–Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure–activity data of the training set indicate that the 2′ position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3′ or 4′ positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3′ and 4′ position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3′,4′-benzo analog, 79. A complementary 2D-QSAR approach—partial least squares analysis using a reduced set of Molconn-Z descriptors—supports the CoMFA structure–activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value.

Differences in serotonin transporter binding affinity in patients with major depressive disorder and night eating syndrome

We examined serotonin transporter (SERT) binding affinity using single photon emission computed tomography (SPECT) in patients with major depressive disorder (MDD) and night eating syndrome (NES). There are similarities between MDD and NES in affective symptoms, appetite disturbance, nighttime awakenings, and, particularly, response to selective serotonin reuptake inhibitors (SSRIs). Six non-depressed patients with NES and seven patients with MDD underwent SPECT brain imaging with 123I-ADAM, a radiopharmaceutical agent selective for SERT sites. Uptake ratios of 123I-ADAM SERT binding were obtained for the midbrain, basal ganglia, and temporal lobe regions compared to the cerebellum reference region. Patients with NES had significantly greater SERT uptake ratios (effect size range 0.64-0.84) in the midbrain, right temporal lobe, and left temporal lobe regions than those with MDD whom we had previously studied. Pathophysiological differences in SERT uptake between patients with NES and MDD suggest these are distinct clinical syndromes.

Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3beta-(substituted phenyl)tropane-2beta-carboxylic acid methyl esters (7a-g), 3beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid esters (8a-j), and 3beta-(4-methoxyphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3Beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC(50) value of 2.5 nM for the DAT and K(i) values of 3.5 and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.

Conformational and electrostatic potential study of the benztropine analogs at the dopamine transporter

Thirty seven stable structures of benztropine analogs were optimized at HF/6-31G(d) and HF/6-311G(d,p) level, respectively. The conformational, electrostatic potential and substituted effects were calculated to evaluate their contribution to the dopamine transporter binding affinities. The results reveal that diphenylmethoxyl group is the active group; the high binding affinities of benztropine are partly caused by high conformational flexibility of diphenylmethoxyl group; the molecular activity will be obviously changed when benzyl-Hs are substituted, which is due to the changes in acreage and intensity of the negative electrostatic potential areas of diphenylmethoxyl group. These results will be useful in designing novel benztropine ligands as dopamine uptake inhibitors and molecular probes for the dopamine transporter.

Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte > MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.

Efficient asymmetric syntheses, determination of absolute configurations and biological activities of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine as a novel potent dopamine uptake inhibitor in the central nervous system

An efficient asymmetric synthesis of the chiral N-(3-chloro-2-hydroxypropyl)anilines ( 2a and 2b) was achieved through the regioselective ring-opening reaction of chiral epichlorohydrin with aniline. This was applied to an asymmetric synthesis of the enantiomers of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1 as a novel potent dopamine uptake inhibitor. Both enantiomers as trihydrochlorides, 4a·3HCl and 4b·3HCl, could be synthesized in good total yields and optical purities of 100% ee in three steps synthesis, respectively. The absolute configurations of 4a·3HCl and 4b·3HCl were determined using the modified Mosher's method with the related compounds, the intermediates ( 2a and 2b) and the free bases ( 4a and 4b). The analytical results indicated that 4a·3HCl and 4b·3HCl have the ( S)- and ( R)-configuration, respectively, and a series of reactions to provide them proceeded without the apparent influence on the stereochemistry at the chiral centers. In in vitro pharmacological evaluations, 4a·3HCl and 4b·3HCl showed potent dopamine transporter binding affinities, high dopamine, moderate serotonin, and weak norepinephrine uptake inhibitory activities, and 4a·3HCl exhibited a more potent and selective dopamine uptake inhibition over the serotonin or norepinephrine uptake inhibition as compared with 4b·3HCl. An ex vivo evaluation revealed that the oral administrations of both enantiomers at a dose of 30 mg/kg in rats displayed apparent dopamine uptake inhibitory activities and 4a·3HCl had a stronger tendency to inhibit dopamine uptake compared with 4b·3HCl.

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity

Background Though selective serotonin reuptake inhibitors have revolutionized the field of psychiatry with demonstrated efficacy in affective and anxiety disorders with minimal side effects, norepinephrine-serotonin reuptake inhibitors may provide efficacy similar to tricyclic antidepressants without the adverse side effects associated with tricyclic antidepressants. Methods The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters. Results Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio = .45). Conclusions Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine. Whether these differences observed in vitro manifest themselves in vivo is not clear.

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity

Greater availability of brain dopamine transporters in major depression shown by [99m Tc]TRODAT-1 SPECT imaging.

Studies of laboratory animals have shown that administration of antidepressants of all pharmacological classes produces changes in dopamine transporter binding affinity. These observations suggest that dopamine transporter function may play a critical role in the pathophysiology of depression. The present study was an examination of the availability of brain dopamine transporter sites in patients with major depression and in healthy comparison subjects. Single photon emission computed tomographic (SPECT) brain scans were acquired for 15 drug-free depressed patients and 46 age- and gender-matched healthy comparison subjects by using [(99m)Tc]TRODAT-1, a selective dopamine transporter imaging agent. Specific regions of interest in the basal ganglia and supratentorial areas of the brain were examined. Specific uptake values of dopamine transporter [(99m)Tc]TRODAT-1 binding affinity were calculated from the SPECT scan data, and the values for the patients and healthy subjects were compared. The specific uptake values of [(99m)Tc]TRODAT-1 binding were significantly higher in the right anterior putamen (23%), right posterior putamen (36%), left posterior putamen (18%), and left caudate nucleus (12%) of the patients than in the comparison subjects. These differences persisted when the data were further analyzed according to gender and age. Dopamine transporter affinity may be higher than normal in the basal ganglia of depressed patients. These findings suggest that dopamine function may be altered in depression and may also be a mechanism of antidepressant activity.

Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter

The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, which were modified at the connective between the diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure–activity relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [ 3H]GBR12935 in rat striatal membranes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC 50 values of nanomolar range. The SAR suggested that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenylamino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity.