[3H]Nipecotic Acid Binding to ?-Aminobutyric Acid Uptake Sites in Postmortem Human Brain

A new potent, blood–brain barrier permeable γ-aminobutyric acid (GABA) uptake blocker, 1-[2-[bis[4-(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) was administered systemically by i.p. injection (5 mg/kg) in Sprague–Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there was a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region. Like the effect of nipecotic acid (applied locally by iontophoresis), the potentiation by CI-966 was clearest when GABA was applied in or near the stratum pyramidale where its action normally is weakest and shows the most pronounced fading. This change in GABA potency is most simply explained by a reduction in GABA uptake.Key words: GABA, muscimol, nipecotic acid, GABA-uptake blocker, epilepsy.

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Structure–activity studies on the inhibition of γ-aminobutyric acid uptake in brain slices by compounds related to nipecotic acid

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-089 ◽

1979 ◽

Vol 57 (6) ◽

pp. 581-585 ◽

Cited By ~ 17

Author(s):

J. D. Wood ◽

D. Tsui ◽

J. W. Phillis

Keyword(s):

Cortical Neurons ◽

Therapeutic Potential ◽

Brain Slices ◽

Aminobutyric Acid ◽

Gaba Uptake ◽

Acid Uptake ◽

Nipecotic Acid ◽

Depressant Action ◽

Methyl Derivatives ◽

Derivatives Of

Various N-methyl derivatives of nipecotic acid and related compounds were tested as inhibitors of γ-aminobutyric acid (GABA) uptake into mini slices. N-Methylnipecotic acid, N,N-dimethyinipecotic acid, N-methylguvacine, and N-methylnicotinic acid were effective inhibitors. None of them, however, were as potent as nipecotic acid itself. All the effective inhibitors, including nipecotic acid, also inhibited the uptake of L-proline, but to a much lesser extent. Four of the test compounds produced a depressant action on cerebral cortical neurons, but even N-methylisoguvacine, the most potent in this respect, was considerably less active than GABA. None of the test compounds caused any clearly discernible changes in the gross behaviour or appearance of mice in the 1-h period following intramuscular injection. It was concluded that methylation of the N atom of nipecotic acid and its derivatives was unlikely to lead to the development of agents with greater experimental or therapeutic potential than that of nipecotic acid itself, if the action of the agent was dependent on its effects on GABA uptake.

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γ-Aminobutyric Acid Uptake Inhibition and Anticonvulsant Activity of Nipecotic Acid Esters

Journal of Pharmaceutical Sciences ◽

10.1002/jps.2600731132 ◽

1984 ◽

Vol 73 (11) ◽

pp. 1612-1616 ◽

Cited By ~ 15

Author(s):

A. Michael Crider ◽

J.D. Wood ◽

Kathryn D. Tschappat ◽

Christine N. Hinko ◽

Karen Seibert

Keyword(s):

Anticonvulsant Activity ◽

Aminobutyric Acid ◽

Acid Uptake ◽

Nipecotic Acid ◽

Uptake Inhibition ◽

Acid Esters

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(R)-N-[4,4-Bis(3-Methyl-2-Thienyl)but-3-en-1-yl]Nipecotic Acid Binds with High Affinity to the Brain ?-Aminobutyric Acid Uptake Carrier

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1990.tb01919.x ◽

1990 ◽

Vol 54 (2) ◽

pp. 639-647 ◽

Cited By ~ 175

Author(s):

Claus Braestrup ◽

Erik B. Nielsen ◽

Ursula Sonnewald ◽

Lars J. S. Knutsen ◽

Knud Erik Andersen ◽

...

Keyword(s):

Aminobutyric Acid ◽

Acid Uptake ◽

Nipecotic Acid ◽

High Affinity ◽

The Brain

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Uptake of γ-Aminobutyric Acid and Glycine by Synaptosomes from Postmortem Human Brain

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1986.tb04523.x ◽

2006 ◽

Vol 47 (2) ◽

pp. 460-467 ◽

Cited By ~ 29

Author(s):

J. A. Hardy ◽

A. Barton ◽

E. Lofdahl ◽

S. C. Cheetham ◽

G. A. R. Johnston ◽

...

Keyword(s):

Human Brain ◽

Aminobutyric Acid ◽

Postmortem Human Brain

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Kinetic Characterization of Inhibition of ?-Aminobutyric Acid Uptake into Cultured Neurons and Astrocytes by 4,4-Diphenyl-3-Butenyl Derivatives of Nipecotic Acid and Guvacine

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1988.tb02986.x ◽

1988 ◽

Vol 50 (3) ◽

pp. 818-823 ◽

Cited By ~ 78

Author(s):

O. M. Larsson ◽

E. Falch ◽

P. Krogsgaard-Larsen ◽

A. Schousboe

Keyword(s):

Aminobutyric Acid ◽

Cultured Neurons ◽

Acid Uptake ◽

Kinetic Characterization ◽

Nipecotic Acid ◽

Derivatives Of

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Phenylalanine Metabolism is Dysregulated in Human Hippocampus with Alzheimer’s Disease Related Pathological Changes

Journal of Alzheimer s Disease ◽

10.3233/jad-210461 ◽

2021 ◽

pp. 1-14

Author(s):

Pan Liu ◽

Qian Yang ◽

Ning Yu ◽

Yan Cao ◽

Xue Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Pathological Examination ◽

Pathological Changes ◽

Targeted Metabolomics ◽

Phenylpyruvic Acid ◽

Postmortem Human Brain ◽

Metabolic Dysregulation ◽

Phenylalanine Metabolism

Background: Alzheimer’s disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated. Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination. Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared. Results: The results show that a pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples. Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation.

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Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

Drug Research ◽

10.1055/a-1290-0119 ◽

2020 ◽

Author(s):

Meenakshi Dhanawat ◽

Sumeet Gupta ◽

Dinesh Kumar Mehta ◽

Rina Das

Keyword(s):

Epileptic Activity ◽

Aminobutyric Acid ◽

Gaba Uptake ◽

Nipecotic Acid ◽

Design Synthesis ◽

Hydrophilic Nature ◽

Carrier Mediated Transport ◽

Ester Prodrug ◽

Hplc Data

Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

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