- Synthesis of Pharmaceutically Relevant 2-Aminotetralin and 3-Aminochroman Derivatives via Enzymatic Reductive Amination
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2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.
- Citoler, Joan,Harawa, Vanessa,Marshall, James R.,Bevinakatti, Han,Finnigan, James D.,Charnock, Simon J.,Turner, Nicholas J.
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supporting information
p. 24456 - 24460
(2021/10/19)
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- Intensification of Free-Radical Racemization for a Non-activated Amine in a Continuous Flow Reactor
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The free-radical racemization of non-activated amines is a powerful tool for process design in the pharmaceutical industry, allowing the recycling of undesired enantiomers after chiral separation. This paper describes the development of the free-radical racemization of a key API intermediate in a continuous flow reactor. Upon development, a significant reduction of the solvent usage and radical initiator was made possible thanks to the conversion into a continuous flow mode. This intensification positively impacted both the environmental footprint and the safety of the reaction as well as maintaining satisfactory productivity.
- Toussaint, Frédéric C.,Defrance, Thierry,Decouvreur, Serge,Carly, Nicolas,Merschaert, Alain
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p. 3389 - 3396
(2020/11/03)
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- Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist
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Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.
- Donthamsetti, Prashant C.,Winter, Nils,Sch?nberger, Matthias,Levitz, Joshua,Stanley, Cherise,Javitch, Jonathan A.,Isacoff, Ehud Y.,Trauner, Dirk
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p. 18522 - 18535
(2018/01/08)
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- Novel Process for the Preparation of Nitrogen Substituted Aminotetralins Derivatives
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The present invention provides an alternative synthesis of N-substituted aminotetralines comprising resolution of N-substituted aminotetralins of formula (II), wherein R1, R2 and R3 are as defined for compound of formula (I).
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Paragraph 0199-0201
(2013/05/08)
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- Structure-activity relationship study of N 6-(2-(4-(1 H -Indol-5-yl)piperazin-1-yl)ethyl)- N 6-propyl-4,5,6,7- tetrahydrobenzo[ d ]thiazole-2,6-diamine analogues: Development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization
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In our effort to develop multifunctional drugs against Parkinson's disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [ 3H]spiroperidol was used to evaluate affinity (Ki) of test compounds. Functional activity of selected compounds in stimulating [ 35S]γS binding was assessed in CHO cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor (for (-)-40Ki, D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45Ki, D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC50, D2 = 114 nM, D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, nonselective D3 agonist (-)-19 (EC50, D2 = 2.96 nM and D3 = 1.26 nM) was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model.
- Johnson, Mark,Antonio, Tamara,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 5826 - 5840
(2012/07/30)
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- NOVEL PROCESS FOR THE PREPARATION OF NITROGEN SUBSTITUTED AMINOTETRALINS DERIVATIVES
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The present invention provides an alternative synthesis of N-substituted aminotetralines comprising resolution of N-substituted aminotetralins of formula (II), wherein R1, R2 and R3 are as defined for compound of formula (I).
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Page/Page column 26
(2012/01/13)
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- Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl) ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson's disease anima
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Here we report structure - activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were
- Ghosh, Balaram,Antonio, Tamara,Zhen, Juan,Kharkar, Prashant,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 1023 - 1037
(2010/08/06)
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- Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl) amino)ethyl)piperazin-1-yl)quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: In vivo activity indicates potential application in symptomatic and neuroprotective therapy for Parkinson's disease
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The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K i). Functional activity of selected compounds was carried out with GTPyS binding assay. SAR results identified compounds (+)-19a and (-)-19b as two potent agonists for both D2 and D3 receptors (EC50 (GTPyS); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in symptomatic and neuroprotective treatment of PD.
- Ghoshs, Balaram,Antonio, Tamara,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 2114 - 2125
(2010/08/20)
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- Further delineation of hydrophobic binding sites in dopamine D 2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5, 6,7,8-tetrahydro-naphthalen-2-ol
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Here we report a structure-activity relationship (SAR) study of analogues of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro- naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (Ki), as measured with tritiated spiperone and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed with the GTPγS binding assay. Compound 8d was the most selective for the D3 receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D2/D3 receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (-)-28b (D2/D3 (ratio of EC50): 105 and 202, respectively) for the D3 receptor and both compounds were more selective compared to the reference drug ropinirole (D2/D3 (ratio of EC50): 29.5).
- Ghosh, Balaram,Antonio, Tamara,Gopishetty, Bhaskar,Reith, Maarten,Dutta, Aloke
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experimental part
p. 5661 - 5674
(2010/10/01)
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- Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor
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Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (Ki; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.
- Brown, Dennis A.,Mishra, Manoj,Zhang, Suhong,Biswas, Swati,Parrington, Ingrid,Antonio, Tamara,Reith, Maarten E.A.,Dutta, Aloke K.
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experimental part
p. 3923 - 3933
(2009/10/10)
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- Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A 2A-D2 receptor heteromers
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Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease.Here, a family of heterobivalent ligands containing a D2R agonist and an A 2AR antagonist linked through a spacer of variable size was designed and synthesized to study A2AR-D2R heteromers. Bivalent ligands with shorter linkers bound to D2R or A2AR with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A2AR-D2R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A2AR-D2R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
- Soriano, Aroa,Ventura, Ruben,Molero, Anabel,Hoen, Rob,Casado, Vicent,Corte, Antoni,Fanelli, Francesca,Albericio, Fernando,Lluís, Carmen,Franco, Rafael,Royo, Miriam
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supporting information; experimental part
p. 5590 - 5602
(2010/03/24)
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- Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2- ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration
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This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the ph
- Biswas, Swati,Zhang, Suhong,Fernandez, Fernando,Ghosh, Balaram,Zhen, Juan,Kuzhikandathil, Eldo,Reith, Maarten E. A.,Dutta, Aloke K.
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p. 101 - 117
(2008/09/20)
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- A novel series of 2-aminotetralins with high affinity and selectivity for the dopamine D3 receptor
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A novel series of N-[4-(4-Phenylbenzoylamino)butyl]-1,2,3,4-tetrahydro-2-naphthylamines with high affinity and selectivity for the dopamine D3 receptor has been prepared. The 5-cyclopropylmethyloxy 3j, methanesulfonyloxy 3k and trifluoromethanesulfonyloxy 3l derivatives represent some of the highest affinity (pKi's 8.6-8.9) and most selective (200-320-fold) dopamine D3 receptor antagonists reported to date.
- Boyfield, Izzy,Coldwell, Martyn C.,Hadley, Michael S.,Johnson, Christopher N.,Riley, Graham J.,Scott, Emma E.,Stacey, Rachel,Stemp, Geoffrey,Thewlis, Kevin M.
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p. 1995 - 1998
(2007/10/03)
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- Affinity for dopamine D2, D3, and D4 receptors of 2-aminotetralins. Relevance of D2 agonist binding for determination of receptor subtype selectivity.
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A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but were never tested in vitro with single receptor subtypes, and these were examined again. None of the tested 2-aminotetralins showed high affinity for the dopamine D4 receptor. However, a number of the 2-aminotetralins showed high affinity for both the D2 and the D3 DA receptors, as exemplified by compounds 11-15 and 21-26, while some had a reasonable selectivity for the DA D3 receptors. The affinities of the 2-aminotetralins for the D21, receptor depended on the type of radioligand (agonist or antagonist) used. The agonist affinity data, obtained by using the agonist ligand [3H]N-0437, are thought to be more relevant for calculating DA receptor subtype selectivity.
- van Vliet,Tepper,Dijkstra,Damsma,Wikstroem,Pugsley,Akunne,Heffner,Glase,Wise
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p. 4233 - 4237
(2007/10/03)
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- Potential Anomalies of Dopamine D-2 Receptor: Challenges for Non-Invasive Imaging Studies by Positron Emission Tomography
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We report our efforts on the development of appropriate radiopharmaceuticals for the non-invasive study of potential anomalies of dopamine D2 receptors in various brain disorders. Agonist-antagonist differences in receptor interactions necessitates that receptor radiopharmaceutical development address the question about the relative sensitivities of the neurotransmitter and radiopharmaceutical in order to detect minor alterations in receptors under various pathophysiological conditions. We are involved in the development of high affinity, selective and reversible antagonists and agonists for the in vivo study of D2 receptor. 18F-Fluorinated substituted benzamides, 18F-fallypride and 18F-desmethoxyfallypride, have now been developed as antagonists. Our efforts are now on the development of fluorinated derivatives of the selective agonist, 5-hydroxy-N-n-propyl-N-phenethyl-aminotetralin as potential radiotracers for the D2 receptors.
- Mukherjee, Jogeshwar,Yang, Zhi-Ying,Brown, Terry,Jiang, Meiying,Kapp, Oscar,et al.
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p. 174 - 192
(2007/10/03)
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- Fluorescent Probes for Dopamine Receptors: Synthesis and Characterization of Fluorescein and 7-Nitrobenz-2-oxa-1,3-diazol-4-yl Conjugates of D-1 and D-2 Receptor Ligands
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Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors.Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl)derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace SCH 23390 and 3H)spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis).The fluorescein derivatives of PPHT andSKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of parent ligands.The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands.The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues.In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor.These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively.The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
- Bakthavachalam, Venkatesalu,Baindur, Nandkishore,Madras, Bertha K.,Neumeyer, John L.
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p. 3235 - 3241
(2007/10/02)
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- Resolution of racemic mixtures
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Racemic 2-(N-propylamino)-5-methoxytetralin is resolved by treating it with a chiral diaroyltartaric acid in an organic solvent at an elevated temperature to form a salt of the amine and chiral diaroyltartaric acid which is soluble in the solvent at the elevated temperature, cooling to precipitate the salt, isolating it, and converting it to the free amine. The product is useful as an intermediate in the synthesis of optionally-active pharmaceutical, such as N-0437.
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