50366-31-9Relevant academic research and scientific papers
A Novel Fluorescent Analog of the Dopamine Reuptake Inhibitor GBR12909
Lavrova,Gretskaya,Akimov,Bezuglov
, p. 416 - 424 (2019)
Abstract: Dopamine transporter is a transmembrane protein associated with regulation of dopaminergic signal transmission by dopamine reuptake from the synaptic cleft back into cytosol. Some neurological disorders, for example Parkinson’s disease, are characterized by dopaminergic neuron degeneration resulting in dopamine level decrease in synapses. Therefore, dopamine transporter may be considered as a potential target in therapy of neurodegenerative disorders. However, the development of molecular tools based on dopamine transporter inhibitors remains challenging, as there is a lack of knowledge about dopamine transporter regulation and distribution in the brain. The sets of tropane and piperazine derivatives synthesized previously are the most common compounds among a number of dopamine reuptake inhibitors. It should be noted that the highest affinity and selectivity to dopamine transporter (compared with serotonin and norepinephrine ones) were demonstrated by an N-substituted piperazine derivative GBR12909. As GBR12909 has high affinity and selectivity, its structure may serve as a base for the development of novel functionalized derivatives. Design of a new fluorescent derivative based on the structure of dopamine transporter antagonist GBR12909 to investigate the transporter localization and dynamics in presynaptic membrane is the aim of this paper. We synthesized a novel fluorescent analog of dopamine transporter derivative GBR12909 labeled by the BODIPY-FL fluorophore. In order to synthesize this compound, a module synthesis scheme was developed. According to this scheme, the basic scaffold contains a linker fragment with protected amino group on the distal end of the molecule. Such scheme allows us to synthesize a set of variable GBR12909 derivatives through conjugation of various functionally significant fragments at the amino group. The first step of the target compound synthesis includes production of 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)piperazine and tert-butyl(6-((4-(3-iodopropyl)phenyl)amino)-6-oxohexyl)carbamate) followed by their ‘assembly’ into one molecule. After the deprotection of the amino group, it was acylated by fluorescent BODIPY-FL-C3 acid. The fluorescent analog was used to investigate its internalization in an experiment with the PC12 pheochromocytoma cells expressing dopamine transporter. Specific accumulation of the fluorescent analog by the cells via the dopamine transporter was demonstrated, the transporter was rather sensitive to GBR12909 inhibition.
Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors
Paudel, Suresh,Acharya, Srijan,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 2266 - 2276 (2017/03/23)
Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50?=?158.7?nM for 5-HT, 99?nM for NE and 97.5?nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
4-phenylsulfonamidopiperidines as calcium channel blockers
-
Page/Page column 38-40, (2009/05/29)
The invention relates to piperidinyl compounds of Formula (I): or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R1-R3 and Z are defined as set forth in the specification. The invention is also directed to an assay useful for identifying such compounds as N-type calcium channel modulators or blockers. The invention is also directed to the compounds of Formula (I) and compounds identified by the above assay, and the use of such compounds to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.
First catalytic enantioselective synthesis of the cocaine abuse therapeutic agent (S)-(+)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol
Forrat, Vicente J.,Ramon, Diego J.,Yus, Miguel
, p. 400 - 405 (2007/10/03)
(S)-(+)-1-(4-{2-[Bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol, which is a promising candidate as a cocaine abuse therapeutic agent, is prepared in several steps. The key asymmetric step is the catalytic enantioselective addition of dimethylzinc to either 2-chloro or 2-bromoacetophenone catalyzed by the use of different chiral isoborneolsulfonamide ligands in the presence of titanium tetraisopropoxide. The synthesis of a new isoborneolsulfonamide ligand bearing a trifluromethyl substituent and its use in this addition is also presented.
Scale-up synthesis of the dopamine uptake inhibitor GBR-12909
Ironside, Michael D.,Sugathapala, Priyantha M.,Robertson, Jerod,Darey, Mark C.P.,Zhang, Jianzhong
, p. 621 - 627 (2013/09/06)
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR-12909) is a dopamine uptake inhibitor. The development of a robust process for the preparation of this compound in kilogram quantities is described. The primary aims of the development work were to eliminate chromatographic purifications, to minimize the use of environmentally unacceptable reagents, and to improve the overall yield of the three-step convergent process. These objectives were met, with significant improvements obtained in the key coupling reaction of N-(3-phenylpropyl)piperazine dihydrochloride salt with 1-[bis(4-fluorophenyl)methoxy]-2-chloroethane, which was previously low-yielding and lacking in reproducibility.
Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1- [2- [bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents
Lewis, David B.,Matecka, Dorota,Zhang, Ying,Hsin, Ling-Wei,Dersch, Christina M.,Stafford, David,Glowa, John R.,Rothman, Richard B.,Rice, Kenner C.
, p. 5029 - 5042 (2007/10/03)
An investigation into the preparation of potential extended-release cocaine-abuse therapeutic agents afforded a series of compounds related to 1- [2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a) and 1-[2-[bis(4- fluorophenyl)methoxy]ethyl]-4-(
New N-(benzhydryloxyalkyl)-4-(carboxy/carbamoylmethyl) piperidine derivatives with antidepressant activity
Ahmad, Y. El,Maillet,Laurent,Talab,Teste,Cedat,Fiez-Vandal,Dokhan,Ollivier
, p. 205 - 218 (2007/10/03)
Several benzhydryloxylalkylpiperidine derivatives were prepared with the aim of obtaining new antidepressant compounds. The influence of the length of the aliphatic chain and of aromatic and piperidine ring substitutions was studied. The pharmacological a
Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of the piperazine ring of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)
Matecka, Dorota,Rothman, Richard B.,Radesca, Lilian,De Costa, Brian R.,Dersch, Christina M.,Partilla, John S.,Pert, Agu,Glowa, John R.,Wojnicki, Francis H. E.,Rice, Kenner C.
, p. 4704 - 4716 (2007/10/03)
The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR
Synthesis and Absolute Configuration of Chiral Piperazines Related to GBR 12909 as Dopamine Reuptake Inhibitors
Matecka, Dorota,Rice, Kenner C.,Rothman, Richard B.,Costa, Brian R. de,Glowa, John R.
, p. 43 - 53 (2007/10/03)
Novel GBR 12909 analogs, enantiomeric trans-2,5-dimethyl-1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazines (+)- and (-)-4 were synthesized. Isomer (-)-4 displayed high affinity (IC 50=3.62 nM) and 34.5 fold enantioselectivity ratio at
