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

Drug Research ◽  
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.

Systemic CI-966, a new γ-aminobutyric acid uptake blocker, enhances γ-aminobutyric acid action in CA1 pyramidal layer in situ

1990 ◽  
Vol 68 (9) ◽  
pp. 1194-1199 ◽  
Author(s):  
U. Ebert ◽  
K. Krnjević
Keyword(s):  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Sprague Dawley ◽  
Nipecotic Acid ◽  
Ca1 Region ◽  
Stratum Pyramidale ◽  
Sprague Dawley Rats ◽  
Pyramidal Layer ◽  
Urethane Anaesthesia

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.

GAT-1 and Reversible GABA Transport in Bergmann Glia in Slices

2002 ◽  
Vol 88 (3) ◽  
pp. 1407-1419 ◽  
Author(s):  
L. Barakat ◽  
A. Bordey
Keyword(s):  
Gaba Receptors ◽  
Receptor Activation ◽  
Bergmann Glia ◽  
Gaba Uptake ◽  
Induced Voltage ◽  
Nipecotic Acid ◽  
Gaba Transporters ◽  
Whole Cell Patch Clamp ◽  
Inward Currents

Although glial GABA uptake and release have been studied in vitro, GABA transporters (GATs) have not been characterized in glia in slices. Whole cell patch-clamp recordings were obtained from Bergmann glia in rat cerebellar slices to characterize carrier-mediated GABA influx and efflux. GABA induced inward currents at −70 mV that could be pharmacologically separated into GABAA receptor and GAT currents. In the presence of GABAA/B/C receptor blockers, mean GABA-induced currents measured −48 pA at −70 mV, were inwardly rectifying between −70 and +50 mV, were inhibited by external Na+ removal, and were diminished by reduction of external Cl−. Nontransportable blockers of GAT-1 (SKF89976-A and NNC-711) and a transportable blocker of all the GAT subtypes (nipecotic acid) reversibly reduced GABA-induced transport currents by 68 and 100%, respectively. A blocker of BGT-1 (betaine) had no effect. SKF89976-A and NNC-711 also suppressed baseline inward currents that likely result from tonic GAT activation by background GABA. The substrate agonists, nipecotic acid and β-alanine but not betaine, induced voltage- and Na+-dependent currents. With Na+ and GABA inside the patch pipette or intracellular GABA perfusion during the recording, SKF89976-A blocked baseline outward currents that activated at −60 mV and increased with more depolarized potentials. This carrier-mediated GABA efflux induced a local accumulation of extracellular GABA detected by GABAA receptor activation on the recorded cell. Overall, these results indicate that Bergmann glia express GAT-1 that are activated by ambient GABA. In addition, GAT-1 in glia can work in reverse and release sufficient GABA to activate nearby GABA receptors.

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

1979 ◽  
Vol 57 (6) ◽  
pp. 581-585 ◽  
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.

Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes 

1995 ◽  
Vol 82 (2) ◽  
pp. 502-511 ◽  
Author(s):  
Jean Mantz ◽  
Jean-Baptiste Lecharny ◽  
Vincent Laudenbach ◽  
Danielle Henzel ◽  
Gilles Peytavin ◽  
...  
Keyword(s):  
Gaba Release ◽  
Volatile Anesthetics ◽  
Rat Striatum ◽  
Gaba Uptake ◽  
Gamma Aminobutyric Acid ◽  
Nipecotic Acid ◽  
Calcium Dependent ◽  
Anesthetic Agents ◽  
Gaba Uptake Inhibitor

Background Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma-aminobutyric acid A (GABAA) receptor-coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization-evoked release of GABA in the rat striatum were investigated. Methods Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with 3H-GABA (20 nM, 5 min, 37 degrees C) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing 3H-GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml.min-1, 37 degrees C) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine. Results More than 95% of 3H-GABA uptake was blocked by a 10(-3)-M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose-related, reversible, noncompetitive, inhibition of 3H-GABA uptake: IC50 = 4.6 +/- 0.3 x 10(-5) M, 5.8 +/- 0.3 x 10(-5) M, 2.1 +/- 0.4 x 10(-3) M, and 4.9 +/- 0.5 x 10(-4) M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium-dependent, concentration-related, increase from basal 3H-GABA release, +34 +/- 10% (P < 0.01) and +61 +/- 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of 3H-GABA elicited by KCl was not affected by any of the anesthetic agents tested. Conclusions These results indicate that most of the intravenous but not the volatile anesthetics inhibit the specific high-affinity 3H-GABA uptake process in vitro in striatal nerve terminals. However, this action was observed at clinically relevant concentrations only for propofol and etomidate. In contrast, the depolarization-evoked 3H-GABA release was not affected by anesthetics. Together, these data suggest that inhibition of GABA uptake, which results in synaptic GABA accumulation, might contribute to propofol and etomidate anesthesia.

scholarly journals γ-Aminobutyric Acid–mediated Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia

2008 ◽  
Vol 109 (6) ◽  
pp. 978-988 ◽  
Author(s):  
Giancarlo Vanini ◽  
Christopher J. Watson ◽  
Ralph Lydic ◽  
Helen A. Baghdoyan
Keyword(s):  
Reticular Formation ◽  
Induction Time ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Breathing Rate ◽  
Pontine Reticular Formation ◽  
General Anesthetics ◽  
Nipecotic Acid ◽  
Mercaptopropionic Acid ◽  
Isoflurane Anesthesia

Background Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. Methods To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Results Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Conclusion Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.

Synthesis of 4,4-bis(2-methylphenyl)-3-butenyl (and butyl) analogs of 4-phenyl-1,4- and 6-phenyl-1,6-dihydropyridine-3-carboxylic acids and their evaluation as neuronal GABA-uptake inhibitors

1997 ◽  
Vol 75 (6) ◽  
pp. 601-610 ◽  
Author(s):  
Nadeem Iqbal ◽  
Zhong-Yong Wei ◽  
Glen B. Baker ◽  
Edward E. Knaus
Keyword(s):  
Catalytic Amount ◽  
Gaba Uptake ◽  
Methyl Nicotinate ◽  
Decomposition Products ◽  
Nipecotic Acid ◽  
Reference Drug ◽  
Uptake Inhibitors ◽  
Ester Moiety ◽  
Gaba Uptake Inhibitors

Treatment of 3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (13) with NaH–DMSO, and then reaction with 1,1-bis(2-methylphenyl)-4-bromobutane (12c) afforded 1-[4,4-bis(2-methylphenyl)butyl]-3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (14). Reaction of methyl nicotinate with 2.1 equivalents 12c or 1,1-bis(2-methylphenyl)-4-bromo-1-butene (11b) afforded 4,4-bis(2-methylphenyl)butyl 1-[4,4-bis(2-methylphenyl)butyl]pyridinium-3-carboxylate bromide (17) or 4,4-bis(2-methylphenyl)-3-butenyl 1-[4,4-bis(2-methylphenyl)-3-butenyl]pyridinium-3-carboxylate bromide (18), respectively. The nonregioselective reaction of the pyridinium salts (17/18) with PhMgCl in THF at −23 °C using a catalytic amount of CuI afforded a mixture of isomeric 4-phenyl-1,4-dihydropyridyl (21 or 22) and 6-phenyl-1,6-dihydropyridyl (27 or 28) products in a ratio of approximately 1:1. All attempts to hydrolyze the 4,4-bis(2-methylphenyl)butyl or 3-butenyl ester moiety of 21/22 or 27/28 to a carboxyl group resulted in decomposition products. In contrast, the corresponding 3-(2-cyanoethyl) esters (23, 24, 29, 30) were readily converted to the corresponding carboxyl analogs (25, 26, 31, 32) via a β-elimination reaction of acrylonitrile using the non-nucleophilic base DBU. The 4-phenyl-1,4-dihydropyridyl (14, 25, 26) and 6-phenyl-1,6-dihydropyridyl (27/28 or 31/32) compounds inhibited the in vitro uptake of [3H]GABA into striatal prisms in the 21–44% range at a 10−4 M test compound concentration, relative to the reference drug nipecotic acid (87% inhibition). Structure–activity correlations showed the dihydropyridyl C-3 substituent was a determinant of [3H]GABA uptake where the potency order was CO2H > 2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl) > CO2(CH2)3CH-(o-tolyl)2 and CO2(CH2)2CH=C-(o-tolyl)2. Compounds possessing C-3 and (or) N-1 CO2(CH2)3CH-(o-tolyl)2 substituents were generally more potent than analogs having CO2(CH2)2CH=C-(o-tolyl)2 substituents. In general, 1,6-dihydropyridyl compounds were more potent than the corresponding 1,4-dihydropyridyl isomers. Keywords: 1,4- and 1,6-dihydropyridines, GABA-uptake inhibitors.

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