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PubMedDate not supplied

Release of [3H]- and endogenous GABA from slices of the rat medulla oblongata: modification by 3-mercaptopropionic acid, nipecotic acid and diaminobutyric acid.

Slices of the rat medulla oblongata were superfused and electrically stimulated. The amount of [3H]- and endogenous GABA was determined. There was a stimulus-evoked release of [3H]- and endogenous GABA, which was Ca2+-dependent and tetrodotoxin-sensitive. 3-Mercaptopropionic acid (3-MP) reduced the release of endogenous GABA, whereas the release of [3H]-GABA was not affected by this agent. Nipecotic acid enhanced the spontaneous and stimulus-evoked release of both [3H]- and endogenous GABA. 3-MP, nipecotic acid and diaminobutyric acid modified the stimulus-evoked release of endogenous GABA from slices containing the rostral ventrolateral medulla, the caudal ventrolateral medulla or the nucleus tractus solitarii, regions responsible for blood pressure regulation. These results suggest that 3-MP inhibits the stimulus-evoked release of GABA without affecting its release process, whereas nipecotic acid enhances the release via its uptake inhibition action.

3-Mercaptopropionic Acid↗
PubMed1989

Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.

Animals↗
PubMed1983

Efflux and exchange of gamma-aminobutyric acid and nipecotic acid catalysed by synaptic plasma membrane vesicles isolated from immature rat brain.

The mechanism of gamma-aminobutyric acid translocation in synaptic plasma membrane vesicles from rat brain has been probed by comparing the ion dependency of net efflux with that of exchange. Furthermore the question has been asked if the same mechanism operates for other solutes translocated by this transporter. Dilution-induced efflux of gamma-aminobutyrate from the membrane vesicles is about 3-fold stimulated by externally added gamma-aminobutyrate. Half maximal stimulation is obtained at a gamma-aminobutyrate concentration similar to the Km for gamma-aminobutyrate influx. This stimulation (exchange) is dependent on external sodium but not on external chloride. In contrast to this gamma-aminobutyrate influx is absolutely dependent on the simultaneous presence of sodium and chloride ions (Kanner, B.I. (1978) Biochemistry 17, 1207-1211), while efflux is dependent on the presence of these two ions on the inside (Kanner, B.I. and Kifer, L. (1981) Biochemistry 20, 3354-3358). Nigericin stimulates dilution-induced efflux of gamma-aminobutyrate from potassium loaded vesicles to a larger extent than external gamma-aminobutyrate. gamma-Aminobutyrate further enhances the nigericin-induced stimulation, provided that the vesicles are not preloaded with chloride. Nipecotic acid is transported with the same features as gamma-aminobutyrate and the two solutes behave similar with respect to the ion dependence of net flux and exchange. A model for the translocation cycle is proposed in which at least one of the translocated sodium ions binds to the transporter in its 'outside' conformation after chloride and the solute have bound previously. Conversely, the solute is released from its 'inside' conformation prior to chloride and at least one of the sodium ions.

Animals↗
PubMed1985

Metabolism of [3H]nipecotic acid in the rabbit retina.

Nipecotic acid has been demonstrated to block the gamma-aminobutyric acid transport systems. Previous studies have shown that the uptake system is the first transmitter-specific parameter to appear during the development of the rabbit retina. Use of these observations has been made to study the influence on the development of gamma-aminobutyric acid receptors of altering the uptake mechanism by treating newborn pups with nipecotic acid to block GABA transport. The present study of the in vivo metabolism of [3H]nipecotic acid in the CNS measured the changes in the levels of [3H]nipecotic acid in both adult and newborn rabbit retinas after injection of the label into the vitreal chamber. It was found that the effective half-life of [3H]nipecotic acid in the vitreous is about 5 h for adult tissue and 3 h for newborn. In contrast, all retinal fractions retained the label longer, the effective half-lives being about 60 h (adult) and 45 h (newborn). Further, no labeled metabolites of nipecotic acid were detected in either adult or newborn tissue. This study gives evidence that the degradation of nipecotic acid in nervous tissue is minimal and suggests that, although the rate of clearance is faster in neonates, the fate of nipecotic acid in vivo may be similar in both adult and newborn tissues.

Age Factors↗
PubMed1979

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

Various N-methyl derivatives of nipecotic acid and related compounds were tested as inhibitors of gamma-aminobutyric acid (GABA) uptake into mini slices. N-Methylnipecotic acid, N,N-dimethylnipecotic 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.

Action Potentials↗
PubMed1984

gamma-Aminobutyric acid uptake inhibition and anticonvulsant activity of nipecotic acid esters.

n-Alkyl esters of nipecotic acid were prepared by Fischer esterification, and the esters were evaluated against bicuculline-induced seizures in mice. Evaluation of the alkyl esters for inhibition of gamma-aminobutyric acid uptake into mouse whole brain mini-slices revealed that the order of potency was proportional to chain length. The octyl ester inhibited gamma-aminobutyric acid and beta-alanine uptakes by apparently nonspecific mechanisms. A variety of phenyl esters of nipecotic acid were also synthesized utilizing either dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole as the condensing agent. Most of the phenyl esters were potent inhibitors of gamma-aminobutyric acid uptake. The uptake inhibition appeared to involve specific and nonspecific (detergent-like) mechanisms. The m-nitrophenyl and p-nitrophenyl esters were particularly potent against bicuculline-induced seizures in mice.

Alanine↗
PubMed1983

Kinetic analysis of the accumulation of gamma-aminobutyric acid by particulate fractions of rat brain: comparison of the effects of nipecotic acid and cis-3-aminocyclohexane-1-carboxylic acid.

Kinetic analyses indicate that nipecotic acid and cis-3-aminocyclohexane-1-carboxylic acid (cis-3-ACHC) inhibit GABA accumulation by similar mechanisms of action. Both amino acids are competitive inhibitors of particulate GABA accumulation when GABA and the inhibitor are added simultaneously to tissue fractions. However, preincubating the tissue with either amino acid produces noncompetitive inhibition of GABA accumulation at low concentrations of inhibitor and mixed inhibition at higher concentrations. The possible roles of intrasynaptosomal mechanisms and of astroglia in producing these effects are discussed. The most notable difference between cis-3-ACHC and the other amino acid inhibitors of GABA accumulation, such as nipecotic acid, cis-4-OH-nipecotic acid, guvacine, beta-proline, homo-beta-proline, and 2,4-diaminobutyric acid (DABA), is that cis-3-ACHC is approximately 3.5 times more potent as an inhibitor following preincubation. Thus, while cis-3-ACHC does inhibit GABA transport, its major site of action in the synaptosome may be intracellular.

Amino Acids↗
PubMed1988

A comparison of prodrug esters of nipecotic acid.

The relative ability of the enantiomers of the ethyl and m-nitrophenyl esters of nipecotic acid to block convulsions induced by bicuculline and pentylenetetrazol, as well as to block the uptake of GABA into whole brain mini-slices, was studied in mice. Neither (+)ethyl nipecotate hydrogen tartrate [(+)E.Tartrate], which is hydrolyzed to (-)nipecotic acid, nor (-)ethyl nipecotate hydrogen tartrate [(-)E.Tartrate], which is hydrolyzed to (+)nipecotic acid, provided protection against challenge with bicuculline. Both (+)E.Tartrate and (-)ethyl nipecotate hydrochloride [(-)E.HCl], which are hydrolyzed to (-)nipecotic acid, blocked seizures induced by pentylenetetrazol. However, neither (-)E.Tartrate nor (+)ethyl nipecotate hydrochloride [(+)E.HCl], which are hydrolyzed to (+)nipecotic acid, provided significant protection against challenge with pentylenetetrazol. These results agree with the relative ability of these compounds to inhibit the uptake of GABA, where (-)nipecotic acid was more potent than (+)nipecotic acid and (+)E.Tartrate was more potent than (-)E.Tartrate. The enantiomers of m-nitrophenyl-3-piperidinecarboxylate hydrochloride, (+)MNPC.HCl and (-)MNPC.HCl, were almost equi-effective in preventing seizures induced by bicuculline. This lack of significant difference in anticonvulsant activity is in contrast with the ability to inhibit the uptake of GABA, where (-)MNPC.HCl was significantly more potent than (+)MNPC.HCl. Changing the route of administration from subcutaneous to intraperitoneal injection reduced the onset of time of the peak effect and the anticonvulsant potency of (+/-)MNPC.HCl. Cholinergic effects were observed with the administration of (+)E.Tartrate and (-)E.HCl, but not with (-)E.Tartrate, (+)E.HCl, (+)MNPC.HCl or (-)MNPC.HCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

GABA uptake inhibitors. Synthesis and effects on audiogenic seizures of ester prodrugs of nipecotic acid, guvacine and cis-4-hydroxynipecotic acid.

The pivaloyloxymethyl esters 4 and 5 of the amino acid GABA uptake inhibitors guvacine and nipecotic acid, respectively, were synthesized as potential prodrugs. The half-lives of 4 and 5 for conversion into the parent amino acids were determined under approximate physiological conditions in the presence or absence of human serum. Under the former conditions the half-lives for 4 and 5 were 6.3 hr and 0.8 hr, and, in the absence of serum, 15.5 hr and 1.2 hr, respectively. The compounds 4 and 5 were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) to DBA/2 mice and their effects on audiogenic seizures determined. In agreement with earlier findings for 5, all phases of the seizure response of the animals were suppressed by compound 4 at doses above 2mmol/kg i.p. At anticonvulsant doses of compound 4, as well as of 5, side effects such as sedation and impairments of motor activities were observed. The ethyl and pivaloyloxymethyl esters 9 and 11 of cis-4-acetoxynipecotic acid, designed as 'double' ester prodrugs of the GABA uptake inhibitor cis-4-OH-nipecotic acid, were synthesized and shown to have very weak anticonvulsant effects. Compounds 9 and 11 did, however, show a broad spectrum of cholinergic side effects. These apparent interactions of 9 and 11 with muscarinic cholinergic receptors have been explained on the basis of the similarity of the structures of 9 and 11 to that of the muscarinic agonist 1-methyl-4-acetoxypiperidine. Furthermore, the structural similarity of 9 and the muscarinic agonist nipecotic acid ethyl ester may, to some extent, underlie the cholinergic profile of 9.

Acoustic Stimulation↗
PubMed1996

Pharmacokinetic and pharmacodynamic analysis of (E)-2-ene valproyl derivatives of glycine and valproyl derivatives of nipecotic acid.

GABA is a major inhibitory neurotransmitter in mammals, whose uptake in glial cells is inhibited by nipecotic acid. In addition to GABA, glycine is an important inhibitory neurotransmitter. Valproic acid (VPA) is one of the four established antiepileptics and (E)-2-ene valproic acid ((E)-2-ene VPA) is its major active metabolite. The described structure-pharmacokinetic-pharmacodynamic relationship (SPPR) study explored the possibility of utilizing valproyl derivatives of glycine and nipecotic acid as new antiepileptics. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following conjugation products were investigated: (E)-2-ene valproyl glycinamide (between (E)-2-ene VPA and glycinamide) and valproyl nipecotic acid and valproyl nipecotamide (between VPA and nipecotic acid). Out of the investigated compounds only (E)-2-ene valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic and pharmacodynamic profile. (E)-2-ene valproyl glycinamide was more potent than VPA and showed an activity and a safety margin similar to those of its analogous compound valproyl glycinamide. The investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDSs) of glycine or nipecotic acid, but, rather, acted as drugs on their own. (E)-2-ene valproyl glycinamide was partially excreted unchanged in the urine (fe = 7.4%), while its urinary metabolite was (E)-2-ene valproyl glycine. Unlike the new antiepileptic tiagabine, in which nipecotic acid is attached to 4, 4-di-(3-methylthien-2-yl)-3-butenyl and yields an active compound, the conjugation between nipecotic acid or its amide and VPA yielded inactive entities. In contrast to nipecotic acid, the conjugation between VPA or (E)-2-ene VPA and glycinamide gave two active compounds with similar pharmacokinetic and pharmacodynamic profiles.

Animals↗
PubMed1990

[3H]nipecotic acid binding to gamma-aminobutyric acid uptake sites in postmortem human brain.

Binding of [3H]nipecotic acid, a proposed marker for GABAergic neurons, was investigated in postmortem human brain by use of a centrifugation assay. Binding was displaceable, apparently saturable, and to a single site, with typical KD and Bmax values of 1.85 microM and 124.2 pmol/mg of protein in the hippocampus. Regional distribution studies indicated a heterogeneous population of [3H]nipecotic acid binding sites with highest concentrations in the lateral globus pallidus. Putamen tissue from four cases of Huntington's disease showed a marked reduction in [3H]nipecotic acid binding. Binding correlated with both age and postmortem delay in the hippocampus. There was an effect of agonal state in which prolonged illness before death apparently caused a reduction in binding. Our results indicate that [3H]nipecotic acid may be used successfully as a marker for neuronal GABAergic uptake sites in human brain, but that the effects of variables such as age, postmortem delay, and agonal state must always be taken into account.

Aged↗
PubMed1981

Comparison between (RS)-nipecotic acid and GABA transport in cultured astrocytes: coupling with two sodium ions.

The sodium ion dependency of the uptake of (RS)-nipecotic acid into astrocytes in primary cultures has been studied by performing kinetic analysis at different sodium ion concentrations (16--151 mM). Vmax of the saturable component of the astroglial (RS)-nipecotic acid uptake is clearly affected by the sodium ion concentration whereas Km surprisingly remains unaffected. At high (RS)-nipecotic acid concentrations (Greater Than or Equal To 50 mu M), uptake rates as a function of the sodium ion concentration were clearly sigmoid. This sigmoid shape was not obvious at lower concentrations of (RS)-nipecotic acid. The calculated Hill coefficients corresponding to all (RS)-nipecotic acid concentrations studied were approximately two. From these results it is concluded that (RS)-nipecotic acid uptake into astrocytes in primary cultures, like astroglial GABA uptake, requires the binding of at least two sodium ions per (RS)-nipecotic acid molecule transported.

Animals↗
PubMed1988

Nipecotic acid enhances synaptic transmission in the frog optic tectum by an action independent of GABA uptake inhibition.

In the frog optic tectum maintained in vitro at 7 degrees C to depress gamma-aminobutyric acid (GABA) transport systems the GABA uptake inhibitor nipecotic acid reversibly enhanced field potentials evoked by optic nerve stimulation. This effect was dose dependent and picrotoxin sensitive. Responses to low concentrations of GABA agonists were not affected by nipecotic acid, whereas responses to the maximal muscimol concentration were depressed. It is suggested that in addition to its well known inhibitory action on GABA uptake systems, nipecotic acid can evoke GABA mimetic effects whose precise origin is presently unclear.

Animals↗
PubMed1984

Anticonvulsant activity of the nipecotic acid ester, (+/-)-m-nitrophenyl-3-piperidinecarboxylate.

The nipecotic acid ester, (+/-)-m-nitrophenyl-3-piperidinecarboxylate hydrochloride (MNPC) is a potent inhibitor of uptake of GABA in vitro and should be able to penetrate into the brain much more readily than the parent compound nipecotic acid. A study of the effects of MNPC on convulsions induced by chemicals which interfere with GABA-mediated neurotransmission was carried out in the mouse, with MNPC being administered by subcutaneous injection 30, 60 or 90 min prior to challenge with bicuculline. It was found that MNPC protected against convulsions induced by bicuculline with ED50 values for clonic and tonic convulsions of 157.8 and 138.8 mg/kg, respectively, at the time of peak effect of 60 min and MNPC abolished both the clonic and tonic components of isoniazid convulsions with respective ED50 values of 255.3 and 76.7 mg/kg at 1 hr. Picrotoxin and pentylenetrazol-induced seizures were also blocked with corresponding ED50 values for clonic convulsions of 224.9 and 235.9 mg/kg at 1 hr. No serious side effects were observed during the 90 min period after the administration of MNPC in doses up to 600 mg/kg.

Animals↗
PubMed1992

[3H]nipecotic acid binding to GABA uptake sites in human brain.

The binding of [3H]nipecotic acid to frozen post-mortem human brain tissue has been characterized. Competition experiments with gamma-aminobutyric acid (GABA), GABA uptake inhibitors, ligands active at post-synaptic GABA receptors and receptors for other neurotransmitter systems, suggest that [3H]nipecotic acid binds to the neuronal (but not glial) GABA uptake site. Competition and kinetic experiments suggest that 85% of the binding is to a high affinity site. The dissociation constants (Kd) measured in kinetic and equilibrium experiments were in the same range (0.5-0.6 microM). The regional distribution was studied in 19 brain regions and the binding was relatively homogenous. It is concluded that [3H]nipecotic acid binding can be used as a marker for neuronal GABA uptake sites in post-mortem human brain tissue.

Aged↗
PubMed1986

Uptake of GABA and nipecotic acid in astrocytes and neurons in primary cultures: changes in the sodium coupling ratio during differentiation.

The coupling ratio between sodium and GABA or the GABA analog, (RS)- nipecotic acid, in neuronal and glial uptake of GABA or nipecotic acid was investigated as a function of the morphological differentiation of these cell types in primary cultures. Both in neurons and astrocytes a high-affinity uptake of GABA and nipecotic acid was observed regardless of the degree of differentiation. The values of Km were essentially identical in undifferentiated and differentiated cells. On the other hand, Vmax was significantly increased both in 10-day-old neurons compared to 1- and 3-day-old neurons and in astrocytes treated with dBcAMP compared to untreated cells, i.e., Vmax increased as a function of differentiation in both cell types. In neurons as well as in astrocytes the morphological differentiation resulted in an alteration in the coupling ratio between sodium and GABA. From calculated Hill coefficients it could be deduced that the coupling ratio between sodium and GABA was changed from 1 to 2 during differentiation. Similar results were obtained for (RS)-nipecotic acid.

Animals↗