Syntheses of 3-carbomethoxy-4-(aryl)piperidines and In vitro and In vivo pharmacological evaluation: identification of inhibitors of the human dopamine transporter

2003 ◽  
Vol 11 (5) ◽  
pp. 775-780 ◽  
Author(s):  
Xianqi Feng ◽  
Keith Fandrick ◽  
Robert Johnson ◽  
Aaron Janowsky ◽  
John R Cashman
Keyword(s):  
Dopamine Transporter ◽  
Pharmacological Evaluation

scholarly journals Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

2021 ◽  
Author(s):  
Marco Niello ◽  
Spyridon Sideromenos ◽  
Ralph Gradisch ◽  
Ronan O'Shea ◽  
Jakob Schwazer ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
In Silico ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Irreversible Binding ◽  
Fast Kinetics ◽  
Slow Dissociation ◽  
Kinetics Of

Abstract α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

scholarly journals In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018

2020 ◽  
Vol 193 ◽  
pp. 172918
Author(s):  
Thomas F. Gamage ◽  
Daniel G. Barrus ◽  
Richard C. Kevin ◽  
David B. Finlay ◽  
Timothy W. Lefever ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Pharmacological Evaluation ◽  
Synthetic Cannabinoid Receptor Agonist

scholarly journals Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4-Aminoquinoline-Based Compounds

2013 ◽  
Vol 4 (12) ◽  
pp. 1198-1202 ◽  
Author(s):  
Matshawandile Tukulula ◽  
Mathew Njoroge ◽  
Efrem T. Abay ◽  
Grace C. Mugumbate ◽  
Lubbe Wiesner ◽  
...  
Keyword(s):  
Pharmacological Evaluation

In Vivo PET Measurements with [11C]PE2I to Evaluate Fetal Mesencephalic Transplantations to Unilateral 6-OHDA-Lesioned Rats

2005 ◽  
Vol 14 (9) ◽  
pp. 655-663 ◽  
Author(s):  
Motoki Inaji ◽  
Takahito Yoshizaki ◽  
Takashi Okauchi ◽  
Jun Maeda ◽  
Yuji Nagai ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
High Performance ◽  
Emission Tomography ◽  
Binding Potential ◽  
In Vitro Autoradiography ◽  
Positron Emission ◽  
Pet Scans ◽  
Mesencephalic Cells

Positron emission tomography (PET) is a useful tool to assess and visualize neurotransmissions in vivo. In this study, we performed repeated PET scans with [11C]PE2I, a tracer of the dopamine transporter, to evaluate the alteration of the expression of dopamine (DA) transmission component after a fetal mesencephalic transplantation. The fetal mesencephalic cells were transplanted into the striatum of unilateral 6-OHDA-lesioned rats. PET scans with [11C]PE2I were performed to evaluate the DA transporter before and 2 and 4 weeks after the transplantation. Rotation behavior tests, in vitro autoradiography, measurements of DA contents in the striatum by high-performance liquid chromatography (HPLC), and tyrosine hydroxylase (TH) immuno-histological examinations were performed at the same time points and examined for their relationship to changes in the dopamine transporter. The number of ipsilateral rotations induced by methamphetamine injections decreased. DA contents in the striatum measured with HPLC significantly increased. In the PET study, the binding potential of [11C]PE2I increased at 4 weeks. The results of the in vitro autoradiography study corresponded with those of the PET study. The degrees of the change in the binding potentials correlated with those of the numbers of rotations in the behavioral study and the DA contents in the striatum. In the histological examination, TH-positive cells with axons were observed at 2 and 4 weeks after the transplantation. As the dopamine transporter exists only in the axon terminal of DA neurons, these results suggested that PET measurements of [11C]PE2I binding indicated not only survival, but maturity and functioning of the transplanted cells. Repeated PET measurements of DA transporters are a useful tool in assessing the effectiveness of neural transplantations.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl]phenyl}thiazoles as atypical antipsychotic agents

2012 ◽  
Vol 22 (4) ◽  
pp. 1660-1673 ◽  
Author(s):  
Kondapalli Venkata Gowri Chandra Sekhar ◽  
Vajja Sambasiva Rao ◽  
Winnie Deuther-Conrad ◽  
Divya Sridhar ◽  
Hunsur Nagendra Nagesh ◽  
...  
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Agents ◽  
Design Synthesis ◽  
Pharmacological Evaluation ◽  
Atypical Antipsychotic Agents

scholarly journals μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

2020 ◽  
Vol 85 (6) ◽  
pp. 711-720
Author(s):  
Ivana Jevtic ◽  
Jelena Penjisevic ◽  
Katarina Savic-Vujovic ◽  
Dragana Srebro ◽  
Sonja Vuckovic ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Opioid Receptor ◽  
General Structure ◽  
D2 Receptors ◽  
Antinociceptive Activity ◽  
D2 Dopamine Receptor ◽  
Pharmacological Evaluation ◽  
Pharmacological Tests

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for ?-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28?42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid?dopamine receptor heterobivalent ligands.

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