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PubMed2001

Short, solubilized polyalanines are conformational chameleons: exceptionally helical if N- and C-capped with helix stabilizers, weakly to moderately helical if capped with rigid spacers.

Isolating spacers introduced between solubilizing lysine regions and a polyalanine core permit rigorous characterization of context-free alanine helices. The preferred building blocks for isolating spacers are amino acids with rigid, extended conformations such as proline, isonipecotic acid, and tert-leucine. Replacing isolating spacers by conventional N- and C-caps dramatically increases the helicity of dodecaalanine. Solubilized, isolated polyalanines provide optimal tools for testing polypeptide helicity algorithms, central to resolution of the protein folding problem.

Alanine↗
PubMed2000

GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects.

In the mid seventies a drug design programme using the Amanita muscaria constituent muscimol (7) as a lead structure, led to the design of guvacine (23) and (R)-nipecotic acid (24) as specific GABA uptake inhibitors and the isomeric compounds isoguvacine (10) and isonipecotic acid (11) as specific GABAA receptor agonists. The availability of these compounds made it possible to study the pharmacology of the GABA uptake systems and the GABAA receptors separately. Based on extensive cellular and molecular pharmacological studies using 23, 24, and a number of mono- and bicyclic analogues, it has been demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as pharmacological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective blockade of neuronal as well as glial GABA uptake in order to enhance the inhibitory effects of synaptically released GABA, or (2) selective blockade of glial GABA uptake in order to increase the amount of GABA taken up into, and subsequently released from, nerve terminals. The bicyclic compound (R)-N-Me-exo-THPO (17) has recently been reported as the most selective glial GABA uptake inhibitor so far known and may be a useful tool for further elucidation of the pharmacology of GABA transporters. In recent years, a variety of lipophilic analogues of the amino acids 23 and 24 have been developed, and one of these compounds, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now marketed as an antiepileptic agent.

Animals↗
PubMed1986

Inhibition of GABA uptake in the rat hippocampal slice.

Pharmacological manipulations known to inhibit GABA uptake prolonged GABA-evoked conductance increases in CA1 pyramidal cells in the rat hippocampal slice preparation. Treatments included reduction of extracellular sodium and exposure to cis-4-OH-nipecotic acid, nipecotic acid or L-2,4-diaminobutyric acid (all at 1 mM). These effects contrast with the results obtained with 4-OH-isonipecotic acid, an inactive structural analog of nipecotic acid, which had no effect on the time-course of GABA responses. 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THPO), an impotent but selective inhibitor of GABA uptake into glia, did not prolong GABA-evoked responses. The effect of sodium reduction depended on the distance between the source of GABA and its receptors, as predicted for an uptake-limited response. GABA-receptor agonists that are poor substrates for GABA uptake (muscimol, thiomuscimol, piperidine-4-sulphonic acid, isoguvacine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) evoked very long conductance changes that were not further prolonged by uptake inhibitors. These results demonstrate the presence of a functional GABA uptake system in the hippocampal slice. The accessibility of hippocampal GABAergic synapses and the known susceptibility of the hippocampus to epileptiform events suggest that the hippocampal slice could be a valuable CNS preparation to study the role of GABA uptake in synaptic physiology.

Aminobutyrates↗
PubMed1985

Gamma-aminobutyric acid uptake and the termination of inhibitory synaptic potentials in the rat hippocampal slice.

Intracellular recordings were made from CA1 pyramidal cells in the rat hippocampal slice to study the processes that influence the time course of inhibitory post-synaptic potentials (i.p.s.p.s) mediated by gamma-aminobutyric acid (GABA), and conductance changes evoked by ionophoretically applied GABA. The GABA-uptake inhibitors, nipecotic acid and cis-4-OH-nipecotic acid (1 mM), greatly prolonged conductance increases associated with both hyperpolarizing and depolarizing responses to ionophoretically applied GABA. In contrast to their effects on GABA-evoked conductances, uptake inhibitors only slightly prolonged antidromically evoked i.p.s.p.s. Their primary effect occurred after the i.p.s.p. had decayed to 5-30% of its peak. 4-OH-isonipecotic acid, a nipecotic acid analogue that does not inhibit GABA uptake, did not prolong i.p.s.p.s or ionophoretically evoked conductance changes. Sodium pentobarbitone (100 microM), a drug that prolongs the open time of GABA-activated chloride channels, potentiated both i.p.s.p.s and responses to ionophoretically applied GABA. Whereas pentobarbitone also prolonged i.p.s.p.s, it did not prolong responses to ionophoretically applied GABA. The prolongation of i.p.s.p.s by pentobarbitone occurred equally in both the early and late phases of the i.p.s.p., in contrast to the effects of GABA-uptake inhibitors. I.p.s.p.s did not usually decay exponentially. The observation that uptake inhibitors prolonged the late but not the early decay phase of the i.p.s.p., together with the previous finding that the conductance change persists for the duration of the i.p.s.p., indicate that GABA is present in the synapse throughout much of the i.p.s.p. These data suggest that diffusion of GABA out of the synapse, a non-exponential process, is an important determinant of the i.p.s.p. decay time course. Increasing the extracellular potassium concentration from 3.5 to 8.5 mM resulted in spontaneously occurring, synchronous burst firing of pyramidal cells. Cis-4-OH-nipecotic acid significantly reduced the number and amplitude of extracellularly recorded population spikes within each burst. We conclude that diffusion, channel open time and GABA uptake all influence the time course of GABA-mediated i.p.s.p.s. The time course of a single, brief i.p.s.p. is determined predominantly by post-synaptic channel kinetics and diffusion of GABA out of the synapse, whereas the inhibition produced by prolonged synaptic bursts or relatively long application of exogenous GABA can be markedly influenced by GABA uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMedDate not supplied

Inhibition of L-carnitine uptake into primary rat cortical cell cultures by GABA and GABA uptake blockers.

L-carnitine plays a central role in mitochondrial function and is found to be differentially distributed in the brain. We have shown before that the uptake of L-carnitine into cultured rat cortical neurones was temperature-dependent, as well as potently inhibited by factors affecting the sodium gradient as well as by molecules resembling its structure, e.g. D-carnitine, acetyl-L-carnitine and gamma-aminobutyric acid (GABA). GABA was the most potent inhibitor of L-carnitine uptake. In the present study we have found that specific GABA uptake blockers, nipecotic acid, cis-4-hydroxynipecotic (HNA), guvacine, 2,4-diaminobutyric acid (DABA) and NO 711 inhibit L-carnitine uptake even more potently than GABA. However, apart from NO 711, they caused about the same maximal inhibition, 67.4% at 50 microM for guvacine, compared to 60.5% by GABA. NO 711 was extremely potent and blocked 80.5% of the L-carnitine uptake. In contrast, the GABAA receptor agonists, isonipecotic acid and isoguvacine, or the antagonist bicuculline, at similar concentrations (50 microM), did not significantly inhibit the uptake of the L-carnitine. However, bicuculline at relatively high concentration (500 microM) was inhibitory (38%). The GABAB receptor agonist, baclofen, or antagonist, phaclofen, were ineffective, although 5-aminovaleric acid did significantly inhibit uptake at both 50 and 500 microM, causing 22 and 48% inhibition respectively. Like bicuculline, it was not as effective as GABA or the specific GABA uptake blockers. The results indicate that the uptake of L-carnitine by rat cortical neurones occurs in part by a process that can be potently inhibited by GABA and GABA uptake blockers.

Animals↗
PubMed2003

Investigation of platelet aggregation inhibitory activity by phenyl amides and esters of piperidinecarboxylic acids.

A series of anilides and phenyl esters of piperidine-3-carboxylic acid (nipecotic acid) were synthesized and tested for the ability to inhibit aggregation of human platelet rich-plasma triggered by adenosine 5'-diphosphate (ADP) and adrenaline. As a rule, amides were about two times more active than the corresponding esters, and derivatives bearing substituents at the para position of the phenyl ring were significantly more active than the meta-substituted ones. Among the tested compounds, 4-hexyloxyanilide of nipecotic acid (18a) was found to be the most active one, its IC(50) value being close to that of the most active bis-3-carbamoylpiperidines reported in literature (ca. 40 micro M) and aspirin (ca. 60 microM) in ADP- and adrenaline-induced aggregation, respectively. Compared with the isomeric 4-hexyloxyanilides of piperidine-2-carboxylic (pipecolinic) and piperidine-4-carboxylic (isonipecotic) acids, compound 18a showed higher activity, and a Hansch-type quantitative structure-activity relationship (QSAR) study highlighted lipophilicity and increase in electron density of the phenyl ring as the properties which mainly increase the antiplatelet activity (r(2)=0.74, q(2)=0.64). The interaction of nipecotoyl anilides with phosphatidylinositol, a major component of the inner layer of the platelet membranes, was investigated by means of flexible docking calculation methods to give an account of a key event underlying their biological action.

Adenosine Diphosphate↗
PubMedDate not supplied

Effects of gamma-aminobutyric acid on the compound action potential of the rat superior cervical ganglion.

The effects on the ganglionic transmission of gamma-aminobutyric acid (GABA) and related drugs were studied in the rat isolated superior cervical ganglion. The extracellularly recorded postganglionic compound action potential was used as an index for ganglionic transmission. GABA reversibly inhibited the ganglionic transmission by blocking the action potential. The effect of GABA is markedly antagonized by bicuculline (20 microM) or picrotoxin (200 microM). Furosemide (1 mM) was also effective in antagonizing the ganglionic effect of GABA. The antagonism by bicuculline was not affected in the presence of pentobarbital (50 microM). Baclofen inhibited the ganglionic transmission through an activation of GABAB receptors since it was markedly antagonized by phaclofen. Muscimol and isoguvacine were less effective than GABA in blocking the ganglionic transmission. The GABA uptake inhibitor isonipecotic acid blocked the ganglionic transmission, probably by activating GABAA receptors, because the effect was antagonized by bicuculline, but the GABA uptake inhibitor guvacine had no significant effect on the ganglionic transmission. These results suggest that GABA causes a ganglionic blockade by activation of both GABAA and GABAB receptor subtypes.

Action Potentials↗
PubMed1986

BRL 20596, a novel anilide with central dopamine antagonist activity.

BRL 20596 (N-(4-amino-5-chloro-2-methoxyphenyl)-1-phenylmethyl-4-piperidine-carbox amide) is a novel anilide related to clebopride (a gastric prokinetic benzamide) in which the sole change is reversal of the amide bond. Previous studies have shown conformational and electronic differences between these molecules which result in the anilide losing its gastric prokinetic activity, whilst retaining its central nervous system activity. Pharmacological and biochemical properties of BRL 20596 are compared here in animals with chlorpromazine, clebopride, haloperidol and sulpiride. BRL 20596 potently inhibited a number of behaviours, such as conditioned avoidance, amphetamine-induced stereotypy and turning, and apomorphine-induced climbing. Homovanillic acid (HVA) levels in the striatum and nucleus accumbens were raised at similar dose levels to those which inhibited these behaviours, whilst sedative activity was only exhibited at much higher dose levels. Haemodynamic changes were only observed with high IV doses of BRL 20596. Much lower doses of sulpiride were needed to raise prolactin levels than to raise HVA levels. This was not the case with BRL 20596 and the other drugs, where the doses needed for the two effects were similar. The results suggest that BRL 20596 is a central dopamine antagonist, with low sedative and haemodynamic activity.

Animals↗
PubMed2002

Xanthamide fluorescent dyes.

Two derivatives of fluorescein, termed "xanthamides," were prepared from fluorescein, an inexpensive dye. Relative to fluorescein, which contains a 6-phenolic OH and a 2'-carboxyl, the first derivative (5) contains a carboxymethyl ether at the 6-position and a secondary amide of dimethylamine at the 2'-position. The second derivative (8) contains a corresponding 6-methyl ether and a secondary amide of isonipecotic acid at the 2'-position. Thus, both derivatives contain a single carboxyl group, making them monofunctional. Especially 8 is much more photostable (about 10 times) than either fluorescein or BODIPY FL dye when exposed to ordinary light (tungsten light bulb). When tested for relative response in a capillary electrophoresis instrument fitted with an argon ion laser detector (488 nm) and a broad band emission filter, 8 was found to be 4-fold less bright than fluorescein. Both xanthamides, consistent with prior literature on 6-O-alkylated fluorescein, exhibit relatively pH-independent fluorescence (pH 4-10 was tested here). Because they possess two absorbance maximums, the xanthamides can be excited over a broader wavelength range than fluorescein or BODIPY. These collective properties of the xanthamides will make them advantageous over fluorescein and BODIPY dyes for some applications.

Boron Compounds↗
PubMed1997

Glycine receptors in cultured chick sympathetic neurons are excitatory and trigger neurotransmitter release.

1. Total RNA isolated from embryonic chick paravertebral sympathetic ganglia was used in a reverse transcription-polymerase chain reaction (RT-PCR) assay with a pair of degenerate oligonucleotide primers deduced from conserved regions of mammalian glycine receptor alpha-subunits. Three classes of cDNA were identified which encode portions of the chicken homologues of the mammalian glycine receptor alpha 1, alpha 2 and alpha 3 subunits. 2. The presence of functional glycine receptors was investigated in the whole-cell configuration of the patch-clamp technique in neurons dissociated from the ganglia and kept in culture for 7-8 days. In cells voltage clamped to -70 mV, glycine consistently induced inward currents in a concentration-dependent manner and elicited half-maximal peak current amplitudes at 43 microM. 3. The steady-state current-voltage relation for glycine-induced currents was linear between +80 and -60 mV, but showed outward rectification at more hyperpolarized potentials. Reversal potentials of these currents shifted with changes in intracellular chloride concentrations and matched the calculated Nernst potentials for chloride. 4. beta-Alanine and taurine were significantly less potent than glycine in triggering inward currents, with half-maximal responses at 79 and 86 microM, respectively. At maximally active concentrations, beta-alanine-evoked currents were identical in amplitude to those induced by glycine. Taurine-evoked currents, in contrast, never reached the same amplitude as glycine-induced currents. 5. The classical glycine receptor antagonist strychnine reversibly reduced glycine-induced currents, with half-maximal inhibition occurring at 62 nM. Two more recently characterized glycine receptor antagonists, isonipecotic acid (half-maximal inhibition at 2 mM) and 7-trifluoromethyl-4-hydroxyquinoline-3-carboxylic acid (half-maximal inhibition at 67 microM), also blocked glycine-evoked currents in a reversible manner. The chloride channel blocker picrotoxin reduced glycine-evoked currents, with half-maximal effects at 348 microM. Inhibition by the glycine receptor channel blocker cyanotriphenylborate was half-maximal at 4 microM. 6. Apart from evoking inward currents, glycine occasionally triggered short (< 100 ms) spike-like currents which were abolished by hexamethonium and thus reflected synaptic release of endogenous acetylcholine. In addition, glycine caused Ca(2+)-dependent and tetrodotoxin-sensitive tritium overflow from neurons previously labelled with [3H]noradrenaline. This stimulatory action of glycine was reduced in the presence of strychnine and after treatment with the chloride uptake inhibitor furosemide (frusemide). 7. In 65% of neurons loaded with the Ca2+ indicator fura-2 acetoxymethyl ester, glycine increased the ratio of the fluorescence signal obtained with excitation wavelengths of 340 and 380 nm, respectively, which indicates a rise in intracellular Ca2+ concentration. 8. The results show that sympathetic neurons contain transcripts for different glycine receptor alpha-subunits and carry functional heteromeric glycine receptors which depolarize the majority of neurons to trigger transmitter release.

Amino Acid Sequence↗
PubMed2004

Activation of single heteromeric GABA(A) receptor ion channels by full and partial agonists.

The linkage between agonist binding and the activation of a GABA(A) receptor ion channel is yet to be resolved. This aspect was examined on human recombinant alpha1beta2gamma2S GABA(A) receptors expressed in human embryonic kidney cells using the following series of receptor agonists: GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), isonipecotic acid, piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid (IAA), 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL) and 5-(4-piperidyl)-3-isoxazolol (4-PIOL). Whole-cell concentration-response curves enabled the agonists to be categorized into four classes based upon their maximum responses. Single channel analyses revealed that the channel conductance of 25-27 pS was unaffected by the agonists. However, two open states were resolved from the open period distributions with mean open times reduced 5-fold by the weakest partial agonists. Using saturating agonist concentrations, estimates of the channel shutting rate, alpha, ranged from 200 to 600 s(-1). The shut period distributions were described by three or four components and for the weakest partial agonists, the interburst shut periods increased whilst the mean burst durations and longest burst lengths were reduced relative to the full agonists. From the burst analyses, the opening rates for channel activation, beta, and the total dissociation rates, k(-1), for the agonists leaving the receptor were estimated. The agonist efficacies were larger for the full agonists (E approximately 7-9) compared to the weak partial agonists ( approximately 0.4-0.6). Overall, changes in agonist efficacy largely determined the different agonist profiles with contributions from the agonist affinities and the degree of receptor desensitization. From this we conclude that GABA(A) receptor activation does not occur in a switch-like manner since the agonist recognition sites are flexible, accommodating diverse agonist structures which differentially influence the opening and shutting rates of the ion channel.

Cells, Cultured↗
PubMed1994

Antibacterial effects of esters of guanidino- and amidino-acids trypsin inhibitors.

Inhibitory effects of various esters of trans-4-guanidinomethylcyclohexanecarboxylic acid and the 4-tert- butylphenyl esters of amidinopiperidine-4-alkanoic, trans-4- amidinocyclohexanealkanoic, trans-4-guanidinoethylcyclohexanecarboxylic and trans-4-guanidinocyclohexanealkanoic acids, all trypsin inhibitors, on the growth of E. coli, B. subtilis, S. aureus and S. epidermidis were examined. 4-tert-Butylphenyl esters strongly inhibited the growth of E. coli and the order of the inhibitory effects correlated with that for the inhibitory effects on proteinase In, which appears immediately before initiation of DNA synthesis in E. coli and closely correlates with the onset of DNA synthesis. No correlation was observed between the inhibitory effects and Ki values for trypsin. The 4-tert-butylphenyl esters also strongly inhibited B. subtilis, S. aureus and S. epidermidis, and the order, of the inhibitory effects on these bacteria roughly coincided with that on E. coli. The order of the inhibitory effects of each ester, on these bacteria was S. epidermidis > S. aureus > B. subtilis > E. coli. Among the esters examined, the biphenyl ester of trans-4-guanidinoethylcyclohexanecarboxylic acid was the most inhibitory on these four bacteria and proteinase In. Hydrolysis of tert-butyloxycarbonyl-L-valyl-L-prolyl-L-arginine 4-methylcoumarin-7-amide, which is a substrate for proteinase In, in crude extracts of E. coli, B. subtilis and S. epidermidis was examined. The order of this activity in these bacteria was E. coli > B. subtilis > S. epidermidis.

Bacteria↗
PubMed1976

[Diphenoxinhydrochloride, a new anti-diarrhea agent].

The new antidiarrheal drug difenoxin hydrochloride is a preparation with a broad range of action; it is suitable for symptomatic treatment of acute and chronic diarrhea of varying etiology and may be administered as additional medication in cases of specific intestinal infections accompanied by diarrhea. Difenoxin hydrochloride was tested in two studies involving 220 patients with acute diarrhea and 41 patients with chronic diarrhea respectively. Side effects were extremely rare and stool frequency and consistency returned to normal at a daily dose of about 6 tablets. This dose could be reduced for the chronic cases after initial treatment with the higher dose. Positive results were obtained within a very short time in more than 80% of the acute cases and in more than 70% of the chronic cases.

Acute Disease↗
PubMed2003

Synthetic methodology utilized to prepare substituted imidazole p38 MAP kinase inhibitors.

In this manuscript, we review the synthetic methods utilized to prepare a variety of imidazole p38 MAP kinase inhibitors. Several methods have been used to prepare the key templates that are discussed; manipulation of the heterocycles around the imidazole core are also considered in the context of their biological activity. Finally, we discuss new synthetic methodologies discovered in our laboratories, which are useful for the preparation of a member of this class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves the thiazolium-catalyzed cross-benzoin condensation of a pyridine aldehyde with an N-acylimine. The pyridine aldehyde was prepared in three steps and 68% yield from 2-chloro-4-cyanopyridine. The tosylamide precursor to the N-acylimine was prepared in two steps and 93% yield from isonipecotic acid. We demonstrate the scope and some preliminary mechanistic studies concerning this new reaction. The resulting alpha-ketoamide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in six steps and 38% overall yield.

Chemistry, Pharmaceutical↗
PubMed1994

Pharmacology of novel GABA receptors found on rod horizontal cells of the white perch retina.

A novel type of GABA receptor is present on rod-driven (H4) horizontal cells of the white perch retina (Qian and Dowling, 1993a). These receptors have been tentatively termed GA-BAC receptors. In this study, the pharmacological properties of these receptors were further investigated by applying several conformationally restricted GABAA receptor agonists, GABAA antagonists, and a GABAB agonist to the H4 horizontal cells. GABA analogs locked in a partially folded conformation had a variety of effects. Isonipecotic acid had no effect on these receptors, whereas isoguvacine activated them but with low potency (EC50 = 137 microM). THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) acted as a competitive antagonist on these receptors with an inhibition constant of 82.5 microM. P4S (piperidine-4-sulfonic acid) activated the receptors at high concentrations (> 1 mM), but at lower concentrations it was a competitive antagonist with an inhibition constant of 80.9 microM. 14AA (imidazole-4-acetic acid), a GABA analog with an extended conformation, potently inhibited the GABA responses on H4 horizontal cells with an inhibition constant of 1.67 microM. Muscimol, which can assume both partially folded and extended conformations, acted as a mixed agonist-antagonist. The GABA responses on H4 horizontal cells were resistant to several competitive GABAA receptor antagonists including bicuculline, hydrastine, and SR-95531, but they were very sensitive to picrotoxin (IC50 = 237 nM). The inhibition by picrotoxin was both competitive and noncompetitive in nature. On the other hand, TBPS (tert-butyl-bicyclophosphorothionate), another GABAA receptor channel blocker, had minimal effects on these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

N-[11C]methylpiperidine esters as acetylcholinesterase substrates: an in vivo structure-reactivity study.

A series of simple esters incorporating the N-[11C]methylpiperidine structure were examined as in vivo substrates for acetylcholinesterase in mouse brain. 4-N-[11C]Methylpiperidinyl esters, including the acetate, propionate and isobutyrate esters, are good in vivo substrates for mammalian cholinesterases. Introduction of a methyl group at the 4-position of the 4-piperidinol esters, to form the ester of a teritary alcohol, effectively blocks enzymatic action. Methylation of 4-N-[11C]methylpiperidinyl propionate at the 3-position gives a derivative with increased in vivo reactivity toward acetylcholinesterase. Esters of piperidinecarboxylic acids (nipecotic, isonipecotic and pipecolinic acid ethyl esters) are not hydrolyzed by acetylcholinesterase in vivo, nor do they act as in vivo inhibitors of the enzyme. This study has identified simple methods to both increase and decrease the in vivo reactivity of piperidinyl esters toward acetylcholinesterase.

Acetylcholinesterase↗