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At least 19 recordsLinked to original sources
PubMed1978

Isoguvacine, isonipecotic acid, muscimol and N-methyl isoguvacine on the GABA receptor in rat sympathetic ganglia.

The GABA-mimetic activities of 4 analogues muscimol, isonipecotic acid, isoguvacine and N-methyl isoguvacine have been examined at the GABA receptor in the rat isolated superior cervical ganglion. The depolarizing action of all 4 analogues could be selectively antagonized by bicuculline methochloride and isopropyl bicyclophosphate. Muscimol was the only analogue more potent than GABA (molar potency ratio = 5.08 +/- 0.707). The potency of isoguvacine was 0.23 +/- 0.026 and isonipecotic acid 0.011 +/- 0.0028. N-methyl isoguvacine was less than 0.001 GABA.

Animals↗
PubMed1985

GABA-mimetic activity and effects on diazepam binding of aminosulphonic acids structurally related to piperidine-4-sulphonic acid.

The relationship between structure, in vivo activity, and in vitro activity of some analogues of the gamma-aminobutyric acid (GABA) agonist piperidine-4-sulphonic acid (P4S) was studied. The syntheses of 1,2,3,6-tetrahydropyridine-4-sulphonic acid (DH-P4S) and (RS)-pyrrolidin-3-yl-methanesulphonamide (PMSA-amide) are described. Like P4S, its unsaturated analogue DH-P4S and the five-ring isomer (RS)-pyrrolidin-3-yl-methanesulphonic acid (PMSA) were bicuculline methochloride (BMC)-sensitive inhibitors of the firing of neurones in the cat spinal cord. Whereas isonipecotic acid was less potent than its unsaturated analogue isoguvacine as a GABA-mimetic and as an inhibitor of GABA binding, the opposite relative potencies of P4S and DH-P4S were observed, P4S being proportionally more potent than DH-P4S. In contrast with P4S and DH-P4S, PMSA, which is an analogue of the potent GABA uptake inhibitor and BMC-sensitive GABA-mimetic homo-beta-proline, was a relatively weak inhibitor of GABA uptake in vitro. PMSA-amide was more than two orders of magnitude weaker than PMSA as an inhibitor of GABA binding and did not significantly affect GABA uptake in vitro. The effects of 3-aminopropanesulphonic acid (3-APS), PMSA, P4S, and DH-P4S on the binding of [3H]diazepam in vitro at 30 degrees C, in the presence or absence of chloride ions, were studied and compared with those of the structurally related amino acids GABA, homo-beta-proline, isonipecotic acid, and isoguvacine. Under these conditions the aminosulphonic acids were weaker than the respective amino acids in enhancing [3H]diazepam binding, the difference being more pronounced in the absence of chloride.

Animals↗
PubMed1988

The action of GABA receptor agonists and antagonists on muscle membrane conductance in Schistocerca gregaria.

1. The properties of postsynaptic gamma-aminobutyric acid (GABA) receptors in the extensor tibiae muscle of Schistocerca gregaria were studied by conventional electrophysiological recording techniques. 2. GABA and other active GABA receptor agonists produced rapid, dose-dependent, reversible increases in membrane conductance. 3. In two microelectrode experiments the ED50 for GABA was approximately 1 mM. In three microelectrode experiments (assuming short cable theory conditions) the ED50 for GABA was 2.3 mM. The Hill coefficient for GABA estimated from the latter experiments was 1.4. 4. The relative potency of muscimol/GABA at the ED50 for GABA was 1.36. 3-Aminopropane sulphonic acid (3-APS) and isonipecotic acid were weakly active, baclofen and piperidine-4-sulphonic acid (P4S) were inactive. Isoguvacine produced depolarizations and increases in conductance in preparations which hyperpolarized in response to GABA. These depolarizations were enhanced by both picrotoxin and pitrazepin although the increases in input conductance were depressed. 5. Picrotoxin (20 microM), (+)-bicuculline (20-100 microM) and pitrazepin (1-10 microM) all reversibly antagonized GABA-induced responses. Such antagonism was not competitive in the case of picrotoxin and (+)-bicuculline but was competitive for pitrazepin. Schild plot analysis gave an average pA2 value of 5.5 for pitrazepin. 6. The significance of these results is briefly discussed.

Animals↗
PubMed1989

Inhibition of acetylcholine storage by acetylcholine analogs in vitro.

Forty-five acetylcholine (AcCh) analogs were chemically synthesized and characterized. They and two commercially available analogs were tested for the ability to inhibit active transport of AcCh by synaptic vesicles purified from the electric organ of Torpedo californica. A range of potencies greater than 4 orders of magnitude was found. A quaternary nitrogen and the presence of the carbonyl group are important to potency. The addition of hydrophobic groups to both ends of isonipecotic acid yielded the most potent analogs, which exhibited a nearly 1000-fold increase in potency relative to AcCh. The probable conformation of AcCh bound by the transporter has been deduced and confirmed by the synthesis of a potent rigid analog based on 2-amino-9-fluorenone. A potent analog was shown to be a competitive inhibitor with respect to AcCh, thus confirming that its site of action is the transporter active site. The structure-activity data clearly distinguish the binding site for AcCh from the site for vesamicol [(--)-(trans)-2-(4-phenylpiperidino)cyclohexanol], which is a noncompetitive inhibitor.

Acetylcholine↗
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↗
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↗
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↗
PubMed1975

Radioimmunoassay for anileridine, meperidine and other N-substituted phenylpiperidine carboxylic acid esters.

Antibodies that bind an 125I-tyramyl derivative of N-succinylanileridine have been produced in animals immunized with N-succinylanileridine-hemocyanin conjugate. Several congeners and metabolites have been tested as competitors of this antigen-antibody reaction. The concentrations (in picomoles) required for 50% inhibition have been found to be: anileridine (0.2), meperidine (3.5), piminodine (3.8), diphenoxylate (20.5), normeperidine (20.0), meperidine acid (45,000) and anileridine acid (3,400). Although ester hydrolysis results in changes in inhibiting capacities on the order of 10(4), major structural changes in the substituent on the nitrogen of the piperidine ring are not readily recognized by the antibody. This radioimmunoassay can be used to study a variety of N-substituted phenylpiperidine carboxylic acid esters by relating the results to the standard curve obtained for the drug under investigation. For all practical purposes, alphaprodine, morphine and methadone do not interfere with the assay.

Animals↗
PubMed1976

[Anesthesia using piritramide and chlorpromazine in dogs].

Piritramide with chlorpromazine in doses of 3 mg kg-1 of live weight causes total anesthesia the intensity of which differs according to the breed and condition of the individual. Anesthesia sets in in 30 to 45 minutes and lasts for 3/4 to 1 1/2 hour. During the anesthesia somatic temperature and frequency of pulse decrease, and even after 24 hours they do not reach the original values. In a majority of cases breathing frequency rises insignificantly, and after 2 to 3 hours it returns to the normal. In single cases there occurs an extreme increase of the number of respirations. The per minute breath volume in the various cases and measurings differs considerably. In the course of anesthesia there occurs an increase of glucose, a decrease of the total protein, an increase of the activity of GPT and GOT, a decrease of the numbers of erythrocytes, of haematocrit and haemoglobin, an increase of pCO2 of the blood, and a decrease of the actual pH of the blood. In the number of leucocytes no changes occurred. The changes in the BE were insignificant. All deviations, except the deviations of the pulse and of the temperature, return to the original values within 24 hours. In the ECG there occurred a fluctuation in the forming of emotions and changes of the amplitude values of the QRS group and of the T wave. In the EEG striking periodical complexes of slow waves were found or combinations of slow and rapid frequencies.

Acid-Base Equilibrium↗
PubMed1987

The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma.

Antibodies to diphenoxylic acid, the pharmacologically active metabolite of Lomotil, were successfully used to develop a precise and specific radioimmunoassay for the measurement of diphenoxylic acid in human plasma. The observed cross-reaction of the antiserum with Lomotil (23.5%) and p-hydroxy diphenoxylic acid (2.9%) was not considered to affect significantly the accuracy of the direct determination of diphenoxylic acid in plasma from human volunteers after ingestion of Lomotil tablets. Within-day and between-day coefficients of variation were better than 3 and 6%, respectively, over the concentration range of 3.4 to 255 ng ml-1. Comparable precision could be achieved at 2 ng ml-1 by doubling the volume of sample analyzed. The assay was used to measure plasma concentrations of diphenoxylic acid in 12 human volunteers for up to 24 hr after ingestion of Lomotil (10mg) tablets. Plasma diphenoxyllic acid levels rose to a mean (SE) maximum level of 87.8 (2.7) ng ml-1 3.3 (0.3) hr after dosing. By 24 hr after dosing plasma levls had decreased to 14.26 (1.67) ng ml-1. The appearance and elimination of plasma diphenoxylic acid could be described by a biexponential function. The appearance half-life was calculated to be 0.82 (0.09) hr, and the elimination half-life was 7.24 (0.73) hr.

Diphenoxylate↗