Design,synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug–drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.     

4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design,synthesis and structure–activity relationships

Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5–9 are inhibitors of monoamine reuptake. Structure–activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l–a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.     

Pharmacophore-based discovery of substituted pyridines as novel dopamine transporter inhibitors

Abnormal dopamine signaling in brain has been implicated in several conditions such as cocaine abuse, Parkinson's disease and depression. Potent and selective dopamine transporter inhibitors may be useful as pharmacological tools and therapeutic agents. Simple substituted pyridines were discovered as novel dopamine transporter (DAT) inhibitors through pharmacophore-based 3D-database search. The most potent compound 18 has a K(i) value of 79 nM in inhibition of WIN35,248 binding to dopamine transporter and 255 nM in inhibition of dopamine reuptake, respectively, as potent as cocaine. Preliminary structure-activity relationship studies show that the geometry and the nature of the substituents on the pyridine ring determine the inhibitory activity and selectivity toward the three monoamine transporters. The substituted pyridines described herein represent a class of novel DAT inhibitors with simple chemical structures and their discovery provides additional insights into the binding site of DAT.     

Design,synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors

A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.     

Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors

We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.     

Design,synthesis and docking study of 4-arylpiperazine carboxamides as monoamine neurotransmitters reuptake inhibitors

Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.     

Vinylogous amide analogs of methylphenidate

In an effort to produce compounds with longer durations of action, we attempted to synthesize ketone analogs of methylphenidate which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups. Nevertheless, vinylogous amide by products have been synthesized and tested for activity at dopamine, norepinephrine, and serotonin transporters. The compounds were found to be weak inhibitors of monoamine reuptake despite rigid three dimensional structures that are quite similar to the global minimum of threo-(R,R)-methylphenidate. The structures were confirmed by X-ray crystallography.     

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.     

The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy decidua

The non-neuronal monoamine transporters (OCT1, OCT2, EMT, and PMAT) play a key role in the clearance of monoamines from extracellular compartments. In a previous report we described endometrial distribution and cyclic variation of the vesicular monoamine transporter (VMAT2) mRNA and the neuronal norepinephrine transporter (NET) mRNA. In the present study we used in situ hybridization, real-time PCR and immunohistochemistry to reveal tissue distribution and cyclic variation of mRNA for the non-neuronal monoamine transporters in the human endometrium and early pregnancy decidua. We found that non-neuronal monoamine transporters are predominantly expressed in the stroma. The plasma membrane monoamine transporter (PMAT) mRNA expression peaked in the proliferative phase, whereas the extra-neuronal monoamine transporter (EMT) mRNA expression peaked in the secretory phase. The organic cation transporter 2 (OCT2) mRNA expression was exclusively detected in few scattered stromal cells and OCT1 mRNA was not detected at all. Our present results demonstrate that PMAT, EMT, and OCT2 transporters are expressed in the endometrial stroma and can potentially regulate reuptake of monoamines in general and histamine in particular. Taken together with our previous finding of VMAT2 mRNA in epithelial cells, we suggest a paracrine interaction between stromal and epithelial cells, which may modulate certain steps of the reproductive process.     

Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives

A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.     

Glycosylation of a Vesicular Monoamine Transporter: A Mutation in a Conserved Proline Residue Affects the Activity, Glycosylation, and Localization of the Transporter

Abstract: The role of N -glycosylation in the expression, ligand recognition, activity, and intracellular localization of a rat vesicular monoamine transporter (rVMAT1) was investigated. The glycosylation inhibitor tunicamycin induced a dose-dependent decrease in the rVMAT1-mediated uptake of [³H]serotonin. Part of this effect was due to a general toxic effect of the drug. Therefore, to assess the contribution of each of the glycosylation sites to the transporter activity, the three putative N -glycosylation sites were mutated individually, in combination, and in toto ("triple" mutant). Mutation of each glycosylation site caused a minor and additive decrease in activity, up to the triple mutant, which retained at least 50% of the wild-type activity. No significant differences were found either in the time dependence of uptake or the apparent affinity for ligands of the triple mutant compared with the wild-type protein. It is interesting that in contrast to plasma-membrane neurotransmitter transporters, the unglycosylated form of rVMAT1 distributed in the cell as the wild-type protein. Pro⁴³ is a highly conserved residue located at the beginning of the large loop in which all the potential glycosylation sites are found. A Pro⁴³Leu mutant transporter was inactive. It is remarkable that despite the presence of glycosylation sites, the mutant transporter was not glycosylated. Moreover, the distribution pattern of the Pro⁴³Leu mutant clearly differed from that of the wild type. In contrast, a Pro⁴³Gly mutant displayed an activity practically identical to the wild-type protein. As this replacement generated a protein with wild-type characteristics, we suggest that the conformation conferred by the amino acid at this position is essential for activity.     

Antidepressants and the monoamine masquerade

Neurotransmitter transporters have long been known to recognize related compounds as substrates, resulting in the accumulation and release of so-called "false transmitters." In this issue of Neuron, Zhou et al. show that when serotonin levels are elevated by inhibition of either serotonin reuptake or of monoamine oxidase, dopamine neurons accumulate serotonin. The results suggest that release of serotonin by dopamine neurons may contribute to the effects of multiple major classes of antidepressants.     

Synuclein modulation of monoamine transporters

Although well-studied in the context of neurodegenerative disease, a clear biological function for the synuclein proteins remains elusive. Emerging data indicate a role for synucleins in monoamine neurotransmitter homeostasis. A key regulatory component of monoamine neurotransmission is re-uptake of neurotransmitter by the dopamine transporter, norepinephrine transporter, and serotonin transporter, which are common drug targets in the treatment of depression and other mood disorders. Through interactions with these transporters, the neuronal cytoskeleton, and pre-synaptic scaffolding proteins, α-synuclein, β-synuclein, and γ-synuclein modulate trafficking, expression and function of monoamine transporters at the cell surface, thus playing a central role in regulating monoamine re-uptake.     

当药黄素抗抑郁作用研究

研究当药黄素的抗抑郁作用及其可能的作用机制。研究采用动物行为绝望模型评价当药黄素抗抑郁活性;采用药物交互作用模型探讨其主要作用环节及其可能的作用机制。结果显示当药黄素没有中枢神经兴奋性,能缩短小鼠悬尾和强迫游泳的不动时间;增加5-HTP诱导的小鼠甩头次数,可拮抗利血平引起的小鼠体温下降和眼睑下垂,对育亨宾毒性具有增强作用,但对盐酸色胺所致大鼠惊厥无影响。上述结果表明当药黄素具有抗抑郁活性,其抗抑郁活性可能与抑制5-羟色胺重摄取、增强脑内神经递5-HT神经功能和影响去甲肾上腺素有关;而与抑制体内单胺氧化酶活性无关。     

QSAR study on dual SET and NET reuptake inhibitors: an insight into the structural requirement for antidepressant activity

Monoamine transporters have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against norepinephrine and serotonin transporters, the QSAR study carried out on N-arylmethylpiperidinamine derivatives as known inhibitors of these transporters is presented. The developed model was validated by standard QSAR parameters and through a detailed structural analysis on how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability having a squared cross validated correlation co-efficient of 0.716 and 0.700 respectively for SET and NET inhibition. The squared conventional correlation coefficient was found to be 0.731 for SET antagonism and 0.777 for norepinephrine reuptake inhibition. The study confirmed that the serotonin reuptake inhibitory activity exhibited by the series is largely explained by steric factors of substituents emphasizing the role of size and shape of the inhibitors in making effective inhibitor-SET binding interactions whereas substituent lipophilicity was found to govern inhibitor-NET interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design inhibitors with a much more enhanced potency and selectivity.     

QSAR study on dual SET and NET reuptake inhibitors: An insight into the structural requirement for antidepressant activity

Monoamine transporters have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against norepinephrine and serotonin transporters, the QSAR study carried out on N-arylmethylpiperidinamine derivatives as known inhibitors of these transporters is presented. The developed model was validated by standard QSAR parameters and through a detailed structural analysis on how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability having a squared cross validated correlation co-efficient of 0.716 and 0.700 respectively for SET and NET inhibition. The squared conventional correlation coefficient was found to be 0.731 for SET antagonism and 0.777 for norepinephrine reuptake inhibition. The study confirmed that the serotonin reuptake inhibitory activity exhibited by the series is largely explained by steric factors of substituents emphasizing the role of size and shape of the inhibitors in making effective inhibitor-SET binding interactions whereas substituent lipophiliCIT000y was found to govern inhibitor-NET interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design inhibitors with a much more enhanced potency and selectivity.     

Neurochemical Consequences of Dysphoric State During Amphetamine Withdrawal in Animal Models: A Review

Chronic abuse of amphetamines, such as d-amphetamine (AMPH) and d-methamphetamine, results in psychological dependence, a condition in which the drug produces a feeling of satisfaction and a drive that requires periodic or continuous administration of the drug to produce overwhelming pleasure or to avoid discomfort such as dysphoria. The dysphoric state of AMPH withdrawal has been recognized as depressive syndromes, such as anhedonia, depression, anxiety, and social inhibition, in early drug abstinence. Medication for treatment of the dysphoric state is important for AMPH abusers to avoid impulsive self-injurious behavior or acts that are committed with unconscious or uncontrolled suicidal ideation. However, successful treatments for AMPH withdrawal remain elusive, since the exact molecular basis of the expression of dysphoria has not been fully elucidated. This review focuses on the molecular aspects of AMPH withdrawal as indexed by neurochemical parameters under a variety of injection regimens (for example, levels of brain monoamines and their metabolites, and γ-aminobutyric acid, expression of genes and proteins involved in neuronal activity, and monoamine metabolism and availability) in rodent models which exhibit significant phenotypic features relevant to the syndromes of AMPH withdrawal in humans.     

Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability

The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.     

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression

Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.     

Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.