Soumava Santra

A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones.

A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B).

A Rapid, One-Pot, Microwave-Influenced Synthesis of Spiro-2,5-diketopiperazines via a Cascade Ugi/6-Exo-Trig Aza-Michael Reaction

A rapid, cascade reaction process has been developed to access biologically validated spiro-2,5-diketopiperazines. The facile and environmentally benign method capitalizes on commercially available starting reagents for a sequential Ugi/6-exo-trig aza-Michael reaction, water as a solvent, and microwave irradiation without any extraneous additives.

D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model.

In this article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinsons disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA- and MPP+-induced toxicity in a dose-dependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinsons disease.

Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents.

To investigate structural alterations of the lead triple uptake inhibitor molecule, disubstituted 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol, we have carried out structure-activity relationship (SAR) studies to investigate the effect of alteration of aromatic substitutions and introduction of heterocyclic aromatic moieties on this molecular template. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. SAR results indicate dopamine norepinephrine reuptake inhibitory (DNRI) type activity in thiophene (10g) and pyrrole (10i) derivatives. On the other hand, 3-hydroxyphenyl derivative 10f and 4-methoxyphenyl derivative 10j exhibited a triple reuptake inhibitory (TUI) activity profile, as these molecules exhibited potent uptake inhibition for all the monoamine transporters (K(i) of 31.3, 40, 38.5 and K(i) of 15.9, 12.9, 29.3 for DAT, SERT, and NET for 10f and 10g, respectively). Compound 10f was further evaluated in the rat forced swim test to evaluate its potential antidepressant effect. The results show significant reduction of immobility by TUI 10f at 10 mg/kg dose, indicating potential antidepressant activity.

Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?

The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.

Structural Exploration of (3S,6S)-6-Benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants

To further explore the basic structural motifs (3S,6S)‐6‐benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine and (2S,4R,5R)‐2‐benzhydryl‐5‐(benzylamino)tetrahydro‐2H‐pyran‐4‐ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [3H]DA, [3H]5‐HT, and [3H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (Ki: 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug‐treated rats relative to vehicle, indicating a potential antidepressant property.

Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters

Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.

Development of potent dopamine-norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template.

Current therapy of depression is less than ideal with remission rates of only 25-35% and response rates of 45-60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (Ki (SERT); 0.71 and 2.68nM, respectively) or a potent DNRI profile for compounds 6b and 6h (Ki (DAT/NET); 8.94/4.76 and 13/7.37nM, respectively). Compounds 4g-4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders.

Interaction of D3 preferring agonist (−)-N 6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N 6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264) with cloned human D2L, D2S, and D3 receptors: potent stimulation of mitogen-activated protein kinases and G protein-coupled inward rectifier potassium channels

This study aims to determine the effect of the novel D3 dopamine receptor agonist, D-264, on activation of D3 and D2 dopamine receptor signal transduction pathways and cell proliferation. AtT-20 neuroendocrine cells stably expressing human D2S, D2L, and D3 dopamine receptors were treated with D-264 and the coupling of the receptors to mitogen-activated protein kinase (MAPK) and G protein-coupled inward rectifier potassium (GIRK) channels was determined using Western blotting and whole-cell voltage clamp recording, respectively. D-264 potently activated MAPK signaling pathway coupled to D2S, D2L, and D3 dopamine receptors. The activation of MAPK was more pronounced than the reference agonist quinpirole and was longer lasting. D-264 also activated GIRK channels coupled to D2S, D2L, and D3 receptors. In addition, D-264 dose-dependently induced cell proliferation in AtT-D2L and AtT-D3 cells. These results indicate that D-264 robustly activates GIRK channels and MAPK coupled to D2 and D3 dopamine receptors in AtT-20 cells. D-264 is also a potent inducer of cell proliferation.

Kinetic Products Under Thermal Conditions: Rapid Entry into α/β-D-Galactofuranosides Using Microwave Irradiation and Selective Lewis Acids

A modified Fischer-Lubineau reaction, employing microwave irradiation and selected Lewis acids such as Mn(ClO4)2, Mn(C2H3O2)3, FeCl3, CoCl2, and AgF as independent additives, induces rapid entry into α/β-d-galactofuranosides in very good yield and purity.