Disease relevance of nipecotic acid

• Unlike the E. coli GabP, the B. subtilis GabP: (i) exhibits approx. equal preference for the 3-carbon (beta-alanine, Km=9.6 microM) and the 4-carbon (GABA, Km=37 microM) amino acids, and (ii) resists inhibition by bulky, conformationally constrained compounds (e.g. nipecotic acid, guvacine), which are active against GABA transporters from brain [1].
• Sodium valproate, nipecotic acid and DABA reduced the increase in slow waves seen in the electroencephalogram (EEG) of control rats at pressures above 10-20 ATA; however, only sodium valproate had a beneficial effect on the behavioural signs of the high pressure neurological syndrome (tremor, myoclonus and convulsions) [2].
• These compounds by themselves produced no signs of toxicity, although nipecotic acid caused a long-term decrease in GABA uptake not associated with toxicity [3].
• The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult [4].

Psychiatry related information on nipecotic acid

• The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated [5].
• Furthermore, the spontaneous locomotor activity of treated animals was not altered when compared to control animals but differed from the animals treated with nipecotic acid [6].

High impact information on nipecotic acid

• High affinity GABA transporters GAT1 and GAT4 were more sensitive to inhibition by nipecotic acid [7].
• A nipecotic acid-resistant gamma-aminobutyric acid (GABA) transporter was cloned from a mouse brain cDNA library [8].
• The mechanisms of neurosecretion were evaluated further by inhibition of vesicular release with the use of Ca(2+)-free, Mg(2+)-enriched dialysis fluid and by local perfusion with inhibitors of voltage-dependent synaptic release (1 microM tetrodotoxin) and of GABA reuptake (0.5 mM nipecotic acid) [9].
• Responses to microinjection of GABAB antagonists (CGP-55845A and SCH-90511), the GABAA agonist muscimol, the GABAA antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats [10].
• The voltage responses of GABA, taurine, nipecotic acid, and beta-alanine all showed first-order saturable kinetics with the following Km's: GABA (Km = 160 microM), beta-alanine (Km = 250 microM), nipecotic acid (Km = 420 microM), and taurine (Km = 850 microM) [11].

Biological context of nipecotic acid

• In these animals, central infusions of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid decreased blood pressure only 1 +/- 1, 13 +/- 2 and 8 +/- 3 mm Hg, respectively [12].
• Injection of nipecotic acid, a GABA uptake inhibitor, into the subpallidal area or of procaine, a neural transmission blocker, into the region of the pedunculopontine nucleus, also reduced significantly the hippocampal-induced hyperkinetic response [13].
• Intrathecal treatment with baclofen (GABA B receptor agonist) and nipecotic acid (GABA uptake inhibitor) provided a significant suppression of spasticity, rigidity, H-reflex or motor evoked potentials [14].
• In 2-month-old rats, [3H]-GABA uptake was inhibited by nipecotic acid, a competitive inhibitor of the GABA carrier (IC50 = 3.6 SD 0.3 microM) [15].
• METHODS: Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized [16].

Anatomical context of nipecotic acid

• In both groups of hypertensive rats the pressor response to injection into the nucleus tractus solitarius of the GABA uptake blocking drug nipecotic acid was significantly greater compared with control rats (P < .01 in each model) [17].
• All three GABA uptake systems were present in cortical synaptosomes from the mouse, hamster, and guinea pig, and all three systems were sodium dependent, energy dependent, temperature sensitive, and totally inhibited by nipecotic acid [18].
• Kinetic characterization of inhibition of gamma-aminobutyric acid uptake into cultured neurons and astrocytes by 4,4-diphenyl-3-butenyl derivatives of nipecotic acid and guvacine [19].
• Autoradiographic analyses showed that in vivo treatment with nipecotic acid preferentially blocked accumulation of 3H-GABA into the amacrine cell bodies and processes in the inner plexiform layer [20].
• The dentate gyrus was perfused by means of a dialytrode , using Krebs-Ringer bicarbonate or nipecotic acid solutions [21].

Associations of nipecotic acid with other chemical compounds

• Perfusion with Ca++-free medium and tetrodotoxin, but not nipecotic acid, inhibited the GABA- and muscimol-evoked release of [3H]ACh, thereby indicating that the released ACh was of neuronal origin [22].
• In addition the effect of intrathecal treatment with baclofen (GABAB receptor agonist; 1 microg), nipecotic acid (GABA uptake inhibitor; 300 microg) and dorsal L2-L5 rhizotomy on spasticity and rigidity was studied [14].
• METHODS: Purified synaptosomes were preloaded with [3H]GABA and superfused with buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA metabolism and reuptake, respectively [23].
• An inhibitor of GABA-T (sodium n-dipropylacetate), a GABA agonist (muscimol hydrobromide) and an inhibitor of GABA uptake (R,S) nipecotic acid amide were administered to DBA/2 isolated aggressive mice throughout three successive daily experimental sessions [24].
• The effects of inhibiting gamma-aminobutyric acid-transaminase (GABA-T) with aminooxyacetic acid or with gabaculine and inhibiting GABA uptake with nipecotic acid on dopamine (DA) synthesis in the retina of light-exposed rats were studied [25].

Gene context of nipecotic acid

• Competitive inhibition studies of [3H]-GABA uptake into plasma membrane vesicles from larval and pupal tissues with either unlabeled GABA or the transport inhibitors DABA, nipecotic acid, or valproic acid, revealed differences in affinities [26].
• It is a lipophilic derivative of nipecotic acid that blocks gamma-aminobutyric acid (GABA) reuptake by inhibition of the GAT-1 transportation system, and that has no other significant pharmacodynamic effect [27].
• Neither GABA (100 microM) nor nipecotic acid (300 microM) enhanced the release of cholecystokinin-like immunoreactivity [28].
• We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy [29].
• Local application of nipecotic acid produced responses that could be entirely blocked by a combination of the GABAA receptor antagonist picrotoxin and the GABAB receptor antagonist CGP 35348 [30].

Analytical, diagnostic and therapeutic context of nipecotic acid

• A novel HPLC assay for the determination of nipecotic acid in mouse brain was developed, based on a modification of a reported amino acid analysis procedure [31].
• The peak outward current induced by nipecotic acid was larger in neurons of the kindled (55.4 +/- 5.7 pA, N=30) than the control group (39.8 +/- 4.5 pA, N=28) (P<0.05) [32].
• Pretreatments with implantation of a morphine pellet or with phentolamine (10 micrograms IT) or with reserpine (10 mg/kg SC) did not attenuate this analgesia, yet the analgesia was antagonized by GABA mimetics, such as muscimol (0.1 microgram IC), nipecotic acid (100 mg/kg IP) [33].
• The quantification and identification of PA are accomplished in rat and mouse brain using high performance liquid chromatography with electrochemical detection (LCEC) and nipecotic acid (NPA) as an internal standard [34].

References