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PubMed2004

Transporter-mediated effects of diclofenamic acid and its ascorbyl pro-drug in the in vivo neurotropic activity of ascorbyl nipecotic acid conjugate.

Continuing our studies on SVCT2 ascorbic acid (AA) transporter-mediated drug delivery of neurotropic agents, we have now investigated the in vitro intracellular uptake of Diclofenac (Diclo) and its conjugate (AA-Diclo), both characterized by high affinity for the SVCT2 transporter. We have also investigated the in vivo uptake mechanism of AA-conjugate of Nipecotic acid (AA-Nipec) and the implication of the transporter-mediated effects of Diclo and AA-Diclo. Diclo resulted as a noncompetitive inhibitor of AA transport, but also showed a sodium-dependent and ascorbate-independent uptake, thus implying the possible involvement of specific transporters in the delivery to the brain of Diclo. This result opens a perspective in the discovery of new strategies in the targeting of this drug to the brain. Inhibitory effects of Diclo and AA-Diclo on the SVCT2 transporter were used to study anticonvulsant effects of AA-Nipec, confirming our hypothesis of an SVCT2-mediated transport in its neurotropic activity. AA-Diclo stability has been also investigated: it is hydrolyzed following a first-order kinetics in buffer, plasma (t(1/2) at about 10 h) and whole blood (t(1/2) at about 3 h), suggesting AA-Diclo as a potential candidate to enhance the short half-life of Diclo in vivo.

Animals↗
PubMed1983

Ion dependency of uptake and release of GABA and (RS)-nipecotic acid studied in cultured mouse brain cortex neurons.

The influence of sodium ions on GABA uptake into neurons cultured from cerebral cortex was investigated at sodium concentrations ranging from 16 to 151 mM. Sodium did not affect the Km for GABA uptake but the uptake rates as a function of the sodium concentration was sigmoid at all GABA concentrations studied (1-200 microM). Hill plots of these curves exhibited straight lines with slopes of 1.7-2.1, suggesting that the coupling ratio between sodium and GABA is at least 2. (RS)-Nipecotic acid, a GABA analogue, was transported with high affinity (Km 8.0 +/- 2.1 microM) like GABA, but the Vmax for nipecotic acid was lower than found for GABA (0.664 +/- 0.035 versus 0.955 +/- 0.059 nmol X min-1 X mg-1), suggesting a microheterogeneity of the GABA transport sites. Neurons loaded with the respective tritiated compounds exhibited a pronounced K+-stimulated, calcium-dependent release of both GABA and nipecotic acid indicating that these cultured cells have developed functionally active GABA-ergic synapses.

Animals↗
PubMed1981

[Nipecotic acid, a competitive inhibitor of the net uptake of 3H-GABA by rat brain synaptosomes].

The kinetics of inhibitory effect of nipecotic acid on two different types of 3H-GABA uptake (apparent uptake by intake and net-uptake by predepolarized synaptosomes) was studied. Nipecotic acid was shown to inhibit the net-uptake of 3H-GABA by competitive route. It is concluded that analysis of inhibitory, action of a substance and of its kinetics should by performed with due regard for at least two components; homoexchange of GABA which might reach 50-60% of total radioactivity taken up and the net-uptake of the neurotransmitter.

Absorption↗
PubMed1990

Hydrolysis of nipecotic acid phenyl esters.

The synthesis and anticonvulsant activity of nipecotic acid esters (1a-1f) have been previously reported. It was thought that these prodrug esters underwent hydrolytic conversion to 1 which inhibited GABA uptake, and that both 1 and an intact ester may have caused inhibition of GABA uptake which resulted in the anticonvulsant activity. There is, however, no stability data available to help evaluate these effects. We have determined degradation half-lives (t 1/2) of these phenyl esters dissolved in 10% serum solution or in pH 7.4 buffer (ionic strength = 0.25 adjusted with KCl) at 37 degrees C by monitoring the appearance of a phenolic compound for a period of 12 h with an HPLC method. Utilizing a published method, in vitro [14C]GABA uptake was measured. Results show that the hydrolysis rate in 10% serum solution was faster than that in buffer solution and that half-lives varied between 0.20 and 3.84 h. The uptake inhibition varied between 8.2 and 41.7% at 0.02 mM concentration, and percent GABA uptake inhibition correlated with log t 1/2 (r = -0.9827, p = 0.00045, based on a t test). Our data suggest that at concentrations ranging from 0.02 to 1 mM, inhibition of GABA uptake is mainly due to 1 formed after hydrolysis of 1a-1f.

Animals↗
PubMed2003

Intracerebroventricular injection of muscimol, baclofen or nipecotic acid stimulates food intake in layer-type, but not meat-type, chicks.

This study was designed to compare the effects of muscimol (GABA(A) agonist), baclofen (GABA(B) agonist) and nipecotic acid (GABA uptake inhibitor) on food intake in two chicken strains (meat-type and layer-type chicks). The intracerebroventricular (ICV) injection of all GABA agents induced hyperphagia in layer-type chicks. However, in broiler chicks, there were similar tendencies with muscimol and nipecotic acid but not significantly different. Conversely, ICV injection of baclofen depressed feeding of broiler chicks. These results suggest that there are some differences in central GABAergic systems between these strains of chicks, but GABAergic systems have an important role in the regulation of food intake in neonatal chicks.

Animals↗
PubMed1980

Effects of sodium n-dipropylacetate, muscimol hydrobromide and (R,S) nipecotic acid amide on isolation-induced aggressive behavior in mice.

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. Aggressive responses, measured by an automated device, were inhibited by the highest doses of the three drugs in each daily session. At the lowest doses, sodium, n-dipropylacetate and nipecotic acid amide failed to inhibit aggression in the first session while they were effective in the subsequent sessions. Muscimol was effective in the first session but did not differ significantly from saline in the second and third session. The highest doses of these three drugs did not affect spontaneous motor activity, indicating that the observed drug effects are rather specific.

Aggression↗
PubMed1986

Nipecotic acid, an uptake blocker, prevents fading of the gamma-aminobutyric acid effect.

In rats under urethane, iontophoretic applications of GABA (30-60 nA) in the str. pyramidale of CA1, showed a rapidly fading inhibitory effect. By contrast, GABA had a well-maintained inhibitory effect in str. radiatum. During iontophoresis of nipecotic acid (30-85 nA) identical applications of GABA in str. pyramidale caused a more prominent depression without fading, which suggests that removal of GABA, by uptake, can at least in part account for 'fading'. Nipecotic acid also prolonged the paired-pulse inhibition, presumably by prolonging the duration of inhibitory postsynaptic potentials.

Animals↗
PubMed1983

Intraocular injections of nipecotic acid produce a preferential block of neuronal 3H-GABA accumulation in adult rabbit retina.

A procedure by which the activity of the retinal GABA uptake system can be manipulated in vivo has been developed. Intraocular injections of nipecotic acid, a proported GABA uptake blocker, were administered to adult rabbits every 48 hours for a two-week period. No behavioral or systemic changes were observed. Injections were well-tolerated with less than 10% loss of the tissue caused by physical damage or injection. Biochemical analyses demonstrated a dose-dependent inhibition of 14C-GABA uptake into retinal tissue. No effect on uptake was observed for saline-treated tissue. 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. This treatment may be especially useful in assessing the functional significance of GABA transport in vivo.

Animals↗
PubMed1990

Alcohol and GABA: ethanol intake modifies hippocampal nipecotic acid binding in ethanol-preferring and non-preferring rats.

3H-nipecotic acid (3H-NIP) binding to GABA uptake recognition sites was studied in the hippocampus of 3 groups of male, Long Evans rats: Group 1: ethanol-naive rats (ENR); Group II: ethanol-preferring rats (DR) and non-preferring rats (NDR), which had consumed about 5 g.kg-1.d-1 and 1 g-1.d-1 of alcohol respectively in the form of a 12% ethanol solution prior to 3H-NIP binding analysis; Group III: DR and NDR who had had no access to ethanol for 21 d after the initial exposure of ethanol solution (28 d). Binding studies showed that ethanol drunk by both DR and NDR in Group II decreased 3H-NIP binding (Bmax decreased) with an enhancement of affinity (KD decreased). In rats subjected to withdrawal of ethanol (Group III), affinity of 3H-NIP for GABA uptake sites was higher than in controls (Group I), but lower than in Group II, Bmax in this group being higher than in the 2 other groups. In Group III, KD was higher in DR than in NDR. These results showed that ethanol intake, in a free-choice paradigm, altered 3H-NIP binding, and that differences in ethanol intake between DR and NDR were associated with differences in sensitivity of hippocampal GABA uptake sites. These differences in 3H-NIP binding could either precede ethanol intake, or be a direct result from it. The results, together with data from other laboratories suggest that: 1), 3H-NIP binding sites are involved in the regulation of ethanol intake; 2), 1 factor responsible for individual differences in ethanol response is reflected by the GABA uptake system.

Animals↗
PubMed1992

Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CA1 neurones.

The action of the novel gamma-aminobutyric acid (GABA) uptake blocker, tiagabine, has been studied on isolated GABAergic fast inhibitory postsynaptic potentials (IPSP) and currents (IPSC) in rat hippocampal CA1 pyramidal cells in the slice preparation. Tiagabine (20-50 microM) had little effect on the peak amplitude of the IPSC, but caused a robust increase in the half-width (by 109 +/- 15%). These results contrasted with those obtained using the established uptake blocker, nipecotic acid (100 microM to 1 mM), which reduced the amplitude of the IPSC by 35 +/- 6% and caused only a modest prolongation of the recovery phase. These effects, which were poorly reversible, are probably explained by the fact that nipecotic acid is a substrate for the GABA-uptake carrier and can act as a false transmitter. Tiagabine is not transported by the GABA carrier and results with this substance demonstrate the role of uptake in determining the kinetics of activation of GABAA receptors. Tiagabine is proposed as the blocker of choice for the GABA uptake system.

Animals↗
PubMed1979

Antagonists of angiotensin II containing N-methyl-L-alanine and DL-nipecotic acid in position 7.

[1-sarcosine, 7-N-methyl-L-alanine, 8-isoleucine]-Angiotensin II and [1-sarcosine, 7-DL-nipecotic acid, 8-isoleucine]-angiotensin II were synthesized by the solid-phase method and purified by cation-exchange chromatography and high-pressure liquid chromatography. In the isolated rat uterus these analogs and less than 0.1% of the myotropic activity of angiotensin II and inhibited angiotensin II with pA2 values of 8.2 and 7.8, respectively. In the rat pressor assay (vagotomized ganglion blocked rat) these analogs had 0.9 and 2.8%, respectively, of the pressor activity of angiotensin II. The results show that the proline residue in position 7 of [Sar1,Ile8]-angiotensin II may be replaced by other secondary amino acids without disrupting interactions at angiotensin II receptors.

Amino Acid Sequence↗
PubMed1982

(3H)-muscimol, (3H)-nipecotic acid and (3H)-isoguvacine as autoradiographic markers for GABA neurotransmission.

Retinas from rabbit, goldfish and guinea-pig were exposed to (3H) GABA, (3H)-nipecotic acid and (3H)-isoguvacine either by intravitreal injection in vivo or by incubations in a balanced salt solution and the distribution of radioactivity was then studied with autoradiography. All substances labelled a similar set of presumed amacrine cells. Incubating at 0 degrees C, in 10-(5)M ouabain, or in 10-(3)M GABA inhibited the labelling by (3H)-muscimol whereas bicuculline (10-(4)M), and glycine (10-(3)M) were less efficient blockers. The result is interpreted as a neuronal uptake of (3H)-muscimol rather than as a GABA receptor binding. All the substances except (3H)-isoguvacine also labelled glia to such a degree that neuronal labelling was often disguised in rabbits and goldfish. Glial labelling by muscimol was less pronounced in guinea-pig. (3H)-isoguvacine (tested only in rabbits) gave a strong labelling of cells with the distribution of GABA neurons and only little glial labelling.

Animals↗
PubMed1990

(R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid binds with high affinity to the brain gamma-aminobutyric acid uptake carrier.

(R)-N-[4,4-Bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid (NO 328) has previously been shown to be a potent anticonvulsant in both mice and rats. Here, we report that NO 328 is a potent inhibitor of gamma-[3H]aminobutyric acid [( 3H]GABA) uptake in a rat forebrain synaptosomal preparation (IC50 = 67 nM) and in primary cultures of neurons and astrocytes. Inhibition of [3H]GABA uptake by NO 328 is apparently of a mixed type when NO 328 is preincubated before [3H]GABA uptake; the inhibition is apparently competitive without preincubation. NO 328 itself is not a substrate for the GABA uptake carrier, but NO 328 is a selective inhibitor of [3H]GABA uptake. Binding to benzodiazepine receptors, histamine H1 receptors, and 5-hydroxytryptamine1A receptors was inhibited by NO 328 at 5-30 microM, whereas several other receptors and uptake sites were unaffected. [3H]NO 328 showed saturable and reversible binding to rat brain membranes in the presence of NaCl. The specific binding of [3H]NO 328 was inhibited by known inhibitors of [3H]GABA uptake; GABA and the cyclic amino acid GABA uptake inhibitors were, however, less potent than expected. This indicates that the binding site is not identical to, but rather overlapping with, the GABA recognition site of the uptake carrier. The affinity constant for binding of [3H]NO 328 is 18 nM, and the Bmax is 669 pmol/g of original rat forebrain tissue. The regional distribution of NaCl-dependent [3H]NO 328 binding followed that of synaptosomal [3H]GABA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Three uptake systems in synaptosomes for nipecotic acid and beta-alanine.

An earlier finding that three systems were responsible for the uptake of gamma-aminobutyric acid by synaptosomes was corroborated. In addition, the existence of three uptake systems for RS-nipecotic acid and beta-alanine was demonstrated. We have called these systems high affinity, medium affinity and low affinity uptake systems respectively. In the case of all three substrates, the high affinity system Km values were around 1 microM or less, the medium affinity system Km values were in the range 10-46 microM, and the low affinity system Km values were in the range 290-3400 microM.

Alanine↗
PubMed2005

Thermodynamic study of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated beta-cyclodextrin stationary phase.

Thermodynamic studies were performed on 12 pairs of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated beta-cyclodextrin stationary phase (CP Chirasil-Dex CB). The influence of ester alkyl group structure on interaction with permethylated beta-cyclodextrin (Me-CD) and enantioselectivity was studied. The types of alkyl groups studied included n-alkyl (C1-C5) and groups containing branching at differing locations relative to the chiral center of the molecule. The results show that for a given molecular weight, the n-alkyl esters have stronger interactions with Me-CD than esters containing branched alkyl groups. However, although having weaker interactions with Me-CD, esters containing alpha-branched alkyl groups exhibit higher enantioselectivity than the corresponding n-alkyl or beta-branched isobutyl esters. From the retention data, thermodynamic parameters were estimated using the retention increment method and enthalpy-entropy compensation plots (ln R' versus deltaH) were constructed. The results suggest that ester enantiomers with branching at the alpha-carbon of the ester alkyl group have additional and/or different types of enantioselective interactions with Me-CD than the C1-C5 n-alkyl esters or beta-branched isobutyl ester. In order to obtain a qualitative sense of the interaction with Me-CD, structures of the diastereomeric complexes formed between Me-CD and some of the ester enantiomers were modeled using simulated annealing molecular dynamics.

Indicators and Reagents↗
PubMed1987

(R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors.

Previous reports have suggested that the ethyl ester of (R)-nipecotic acid ethyl ester [(R)-NAEE] displays cholinomimetic properties in vivo. The present study was undertaken to characterize more fully this action by examining the effects of (R)-NAEE in a number of pharmacological and biochemical tests of cholinergic action. (R)-NAEE was found to produce negative inotropic and chronotropic effects on the guinea pig atria (pD2 = 5.91 and 5.62, respectively), and was capable of stimulating contractions in the guinea pig ileum (pD2 = 5.95) and rat jejunum (pD2 = 5.40) at concentrations similar to bethanechol. Both the cardiac and intestinal effects of (R)-NAEE were reversed by atropine. Moreover, (R)-NAEE competed with N-[3H]methylscopolamine and [3H]pirenzepine for muscarinic binding sites in a variety of tissues. Like carbachol, (R)-NAEE inhibited GTP-stimulated adenylate cyclase in rat striatal membranes (EC50 = 52 microM), whereas, unlike carbachol, (R)-NAEE was unable to stimulate inositol phosphate accumulation in rat cerebral cortical slices, behaving as an antagonist in this latter system (pA2 = 5.0). The results indicate that (R)-NAEE interacts directly with cholinergic muscarinic receptors, being an agonist for the M2 subtype and an antagonist at M1 sites.

Adenylyl Cyclase Inhibitors↗
PubMed1980

Effect of picrotoxin and nipecotic acid on inhibitory response of dopaminergic neurons in the ventral tegmental area to stimulation of the nucleus accumbens.

Electrical stimulation of nucleus accumbens inhibited the activity of neurons in the ventral tegmental area (VTA). Inhibition was potentiated by nipecotic acid, a GABA uptake inhibitor, and was attenuated by picrotoxin, a GABA antagonist. Four units inhibited by nucleus accumbens stimulation were also antidromically activated. These observations suggest that neurons in the VTA, including specifically those projecting to the nucleus accumbens, receive a descending GABAergic input from that area.

Animals↗