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PubMed1980

[Behavioral pharmacology of mianserin hydrochloride, a new antidepressant (author's transl)].

Behavioral pharmacological properties of mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzol[c,f]pyrazino [1.2-a]azepine monohydrochloride) were investigated in comparison with imipramine (IMP) and amitriptyline (ATP). Mianserin antagonized reserpine-induced hypothermia but to a much lesser extent than IMP or ATP, and did not block the ptosis evoked by reserpine or tetrabenazine. Amphetamine-induced stereotyped behavior was significantly enhanced by both IMP and ATP, but not by mianserin. Unlike IMP or ATP, haloperidol-induced catalepsy in the rat was not blocked by mianserin. Like IMP or ATP, mianserin did not suppress the convulsions induced by bemegride or strychnine in the mouse, and or emetic action of apomorphine in the dog, while only mianserin did not block the convulsions evoked by electric shocks. Mianserin more strongly potentiated the anesthetic action of thiopental than did IMP. ATP showed strong muscle relaxant action and the impairment of coordinated motor activities both in mice and rats, in the inclinated screen test and rotarod test, while, like IMP, these actions of mianserin were significant only in the rat. Catalepsy was not induced nor was the righting reflex suppressed by mianserin. In the low spinal cat, mianserin did not depress the amplitude of extensor MSR. Moreover, the MSR inhibition induced by conditioning stimulation of ipsilateral cutaneous afferents and the MSR potentiation evoked by conditioning stimulation of contralateral saphenous nerve were unaffected by mianserin. The curious behavior of mice and rats was significantly and dose-dependently suppressed by mianserin, and tended to be suppressed by ATP, while an enhancement was seen with IMP in large doses. Mianserin was the most potent in suppressing the fighting behavior induced by long-term isolation of the mouse, and was the weakest in suppressing electric-stimulation-induced fighting behavior, compared with IMP and ATP. Mianserin showed no significant suppression of the muricide behavior of the olfactory bulbectomized rat, while IMP significantly suppressed it. No significant differences were observed among mianserin, IMP and ATP as to their actions on the conflict behavior and the shuttle-box type conditioned avoidance behavior of the rat. These results indicate that behavioral pharmacological actions of mianserin were not always the same as those of IMP and ATP. Therefore, mianserin may be a new antidepressant with mechanisms of action which differ from that of the usual tricyclic antidepressants.

Agonistic Behavior↗
PubMed1976

[Further results of a multi-centre clinical trial with the oral antidiabetic drug glisoxepide (author's transl)].

The oral antidiabetic agent 1-(hexahydro-1-H-azepin-1-yl)-3-(p-[2-(5-methyl-isoxazol-3-carboxamido)-ethyl]-phenylsulfonyl)-urea (glisoxepide, BS 4231, Pro-Diaban¿) was studied in a multi-centre open clinical trial comprising 4337 patients and was found to be an effective therapeutic agent for maturity-onset diabetics. About 66% of the patients had been pre-treated with oral antidiabetics. 54.7% of those 3572 patients treated with Pro-Diaban for at least 3 months achieved stabilization, which was classified according to strict criteria as "good", 73.4% achieved at least "satisfactory" stabilization. 12.5% of the cases dropped out after having received at least 12 mg/day because of inadequate efficacy of Pro-Diaban; 51.9% of these patients dropped out in the first 3 months (early failures 6.9% of the total case number). 61.9% received their daily dose in one portion, 29% in two and 10% in three portions. 98% received maximally 16 mg, 70% maximally 8 mg, and 42% 4 mg per day. Hypoglycaemic episodes led in 0.9% to a termination of the trial. In 1.22% of the cases the trial was terminated because of side effects, in 0.18% of cases they consisted of allergic or suspected allergic complaints and in 0.69% they consisted mainly of gastro-intestinal symptoms. Of the side-effects which did not lead to a termination of the trial, dizziness, headache and nausea were the relatively more frequent symptoms. An analysis of the laboratory data under consideration of pathological and normal initial and subsequent values showed that under the influence of Pro-Diaban pathological data reverted to normal more frequently than initially normal values changed to pathological ones. The analysis of laboratory and blood pressure data from 4 subgroups of patients, e.g. patients with diseases of the liver or the kidneys and hyperlipaemic or hypertensive patients, revealed that those data of special interest in each subgroup had mostly improved or remained unchanged under Pro-Diaban.

Aged↗
PubMed1976

Clinical and pharmacological effects of treatment with a new antidepressant.

The novel tetracyclic piperazino-azepine compound Org GB 94 (Tolvon, Tolvin) in a dose of 20 mg three times daily was found to be of save markedly and significantly less side-effects. Patients with reactive depression and those with endogenous depression reponded equally well to Org GB 94. No correlation was found between plasma levels of Org GB 94 and either clinical effects or side-effects. Org GB 94 did not alter the tyramine pressor response, in contrast to amitriptyline.

Adjustment Disorders↗
PubMed1993

Role of dopamine D1 receptors in the lethal effects of cocaine and a quaternary methiodide analog.

Acute cocaine overdose can result in convulsions and death although the mechanisms associated with this toxicity are poorly understood. The role of D1 receptors in the central and peripheral actions in cocaine were investigated by comparisons of cocaine with the stable charged cocaine analog, cocaine methiodide. Both cocaine and cocaine methiodide produced dose-related increases in lethality in male, Swiss Webster mice, with cocaine methiodide being slightly more potent than cocaine; however, only cocaine produced convulsions. Several dopamine D1 antagonists ([R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine] (SCH 23390), [(-)-trans-6,7,7a,8, 9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho++ +-(2-1-b)azepin e (SCH 39166), 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline HBr (A-69024), [R-(+)-7-bromo-8-hydroxy-3- methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] (SK F83566)) produced dose-dependent protection against the lethal effects of both compounds. Protection against cocaine methiodide-induced lethality was conferred by lower doses of the D1 antagonists than those effective against cocaine. Stereoselectivity of this effect was demonstrated by the lack of activity of the inactive enantiomer of SCH 23390. The D2 antagonist haloperidol was ineffective against either cocaine- or cocaine methiodide-induced lethality. Lethal effects of the nondopaminergic local anesthetic, lidocaine, were not influenced by prior treatment with D1 antagonists. Lethal effects of cocaine were enhanced by both centrally and peripherally acting D1 agonists but not by the D2 agonist quinpirole. Cocaine methiodide-induced lethality was also enhanced by the peripherally active DA1 agonist, fenoldopam.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Contribution of ligand structure to activation of alpha 2-adrenergic receptor subtype coupling to Gs.

Recently, we have demonstrated that alpha 2-adrenergic receptors (alpha 2AR) functionally couple not only to Gi but also to Gs. This alpha 2AR-Gs coupling was subtype selective, in that the degree of alpha 2AR-Gs (but not -Gi) coupling was different between alpha 2AR subtypes. It is not known whether the determinants of this subtype selectively are found within the ligand-binding region of the receptor or within the intracellular G protein-coupling domains of the individual subtypes. We therefore expressed the three cloned human alpha 2AR (alpha 2C10, alpha 2C4, and alpha 2C2) in Chinese hamster ovary cells and studied the contribution of the ligand-binding domain to functional Gi versus Gs coupling, by determining the ability of various agonists (catecholamines, imidazolines, and azepines) to elicit alpha 2AR-mediated inhibition and stimulation of adenylyl cyclase activity. Isolation of Gi and Gs responses was accomplished by incubating cells with cholera or pertussis toxin, respectively. Although each compound was found to be a full agonist for alpha 2AR-Gi coupling, the efficacy of these agonists to elicit alpha 2AR-Gs coupling was markedly different, not only among drugs but also among the three alpha 2AR subtypes. The most notable differences occurred with the imidazoline agonists. Specifically, oxymetazoline stimulated adenylyl cyclase activity 210 +/- 17% for alpha 2C2 and 22 +/- 2.6% for alpha 2C10 and displayed no stimulation for alpha 2C4. UK-14304 stimulated adenylyl cyclase activity 240 +/- 16% for alpha 2C10, 160 +/- 14% for alpha 2C4, and 86 +/- 9% for alpha 2C2. Overall, the rank order of efficacy of these agonists to elicit stimulation of adenylyl cyclase activity by alpha 2C10 was epinephrine = norepinephrine = UK-14304 > BHT-933 > BHT-920 > oxymetazoline. For alpha 2C4 the rank was epinephrine = norepinephrine = UK-14304, with oxymetazoline, BHT-920, and BHT-933 not eliciting any stimulation. For alpha 2C2 the rank was epinephrine = norepinephrine > oxymetazoline > UK-14304 = BHT-920 > BHT-933. Thus, the coupling of alpha 2AR subtypes to Gs occurs with endogenous catecholamines as well as multiple synthetic agonists, and the degree of Gs coupling is highly dependent on the structure of the agonist. Also, compounds that act as full agonists for Gi coupling are not necessarily full agonists for Gs coupling.

Adenylyl Cyclases↗
PubMed1994

Inhibitory effect of epinastine on bronchoconstriction induced by histamine, platelet activating factor and serotonin in guinea pigs and rats.

Effects of epinastine ((+/-)-3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine hydrochloride, WAL 801 CL, CAS 80012-43-7) and reference drugs on bronchoconstriction induced by histamine, platelet activating factor (PAF) and serotonin were studied in guinea pigs and rats. Oral administration of epinastine resulted in a potent inhibition on bronchoconstriction induced by all three bronchoconstrictor agents, and especially, an inhibitory effect on histamine-induced response was remarkable. The effect of epinastine was stronger than that of ketotifen in inhibiting the responses induced by both PAF and serotonin. However, the extent of inhibition in the latter was less remarkable than that seen after histamine. Azelastine was 1.36-4.57 times less potent than epinastine in inhibiting the bronchoconstriction induced by either bronchospasmogen. Although promethazine displayed inhibitory effects on the responses induced by histamine, PAF and serotonin, the inhibiting potency was distinctly inferior to that of epinastine.

Airway Resistance↗
PubMed1994

The behavioral effects of the stereoisomers of 4-methylaminorex, a psychostimulant, in the rat.

In this study, we examined the effect of the isomers of the psychostimulant 2-amino-4-methyl-5-phenyl-delta 2-oxazoline (4-methylaminorex or 4-MAX) on behavior in rats. The s.c. administration of the stereoisomers of 4-MAX, trans-4S,5S, cis-4R,5S, cis-4S,5R and trans-4R,5R (0.3-3 mg/kg), produced a dose-dependent increase in locomotor activity. However, at a dose of 10 mg/kg, the isomers of 4-MAX produced an initial increase in locomotor activity followed by the appearance of stereotyped behaviors (continuous sniffing, chewing, head bobbing, etc.) then a subsequent phase of rebound-enhanced locomotor activity all over a time course of 4 hr. The rank order of potency for the stereoisomers of 4-MAX was: 4S,5S > 4R,5S =4S,5R < 4R,5R. To determine what neurotransmitter systems may mediate the action of 4-MAX, the ability of various receptor antagonists to block or attenuate the effect of trans-4S,5S-4-MAX (3 mg/kg s.c.) on locomotor activity was examined. The selective dopamine (DA) D1 antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo- [d]naph-thio[2,1b]azepine (SCH 39166) and the D2 receptor antagonist (-)-eticlopride significantly, attenuated the behavioral action of trans-4S,5S-4-MAX, whereas antagonists to serotonergic and adrenergic receptors were ineffective. These results suggest that the ability of 4S,5S-4-MAX to induce locomotor hyperactivity and stereotypical behaviors and to increase rearing durations is primarily mediated by DA receptors. To determine whether the action of 4-MAX is dependent upon 5-hydroxytryptamine or DA concentrations in nerve terminals, rats were pretreated with either reserpine, alpha-methyl-p-tyrosine or d,l-p-chlorophenylalanine. Both reserpine and alpha-methyl-p-tyrosine pretreatment markedly attenuated the locomotor activity produced by trans-4S,5S-4-MAX. Moreover, L-dopa partially reversed the inhibitory action of alpha-methyl-p-tyrosine on 4S,5S-4-MAX-induced behavioral activation. In contrast, the administration of d,l-p-chlorophenylalanine did not alter the behavioral responses produced by trans-4S,5S-4-MAX. Taken together, our results suggest that 4-MAX may increase several locomotor behaviors by inducing neuronal DA release, which subsequently interacts with dopaminergic receptors.

Animals↗
PubMed1994

Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline.

In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Modification of the behavioral effects of the selective dopamine D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine by dopamine antagonists in monkeys.

The present studies were conducted to evaluate the modification of the behavioral effects of the selective D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] by dopamine receptor blockade. In squirrel monkeys responding under a fixed-ratio schedule of stimulus-shock termination, the effects of (+)-PHNO were determined alone and in combination with the selective D2 antagonist eticlopride, the selective D1 antagonist (-)-trans-6,7,7a,8,9,13b- hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1)azepine (SCH 39166), the nonselective D1/D2 antagonist cis-flupentixol or the atypical neuroleptic clozapine. When administered alone, (+)-PHNO produced dose-dependent decreases in rates of responding. Pretreatment with eticlopride and cis-flupentixol resulted in dose-dependent right-ward shifts of the (+)-PHNO dose-effect curve, indicative of surmountable antagonism. Pretreatment with SCH 39166 and clozapine failed to antagonize the effects of (+)-PHNO and resulted in a downward shift of the (+)-PHNO dose-effect curve. Other experiments were conducted to determine the duration of either catalepsy-associated behavior or repetitive scratching produced by (+)-PHNO alone and in combination with selected dopamine receptor blockers. Low doses of (+)-PHNO (0.001-0.003 mg/kg) increased the duration of catalepsy-associated behavior, whereas higher doses (0.003-0.01 mg/kg) restored the duration of catalepsy-associated behavior to control values and produced increases in the duration of repetitive scratching.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Neurochemical and behavioral evidence that Ro 41-9067 is a selective presynaptic dopamine receptor agonist.

(-)-2,3,4a,5,6,10b-Hexahydro-7-hydroxy-2-methylbenzo(f)-quinoline 4(1H)-ethanol (Ro 41-9067) was compared with apomorphine, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine (B-HT 920), lisuride and other dopamine (DA) receptor agonists in a series of tests designed to characterize its pharmacological activity on DA receptors. In vitro binding studies indicated that Ro 41-9067 bound selectively to DA D2 vs. D1 receptors. It also had a moderate affinity for serotonin1A and alpha-2 adrenergic receptors. Ro 41-9067 exhibited a marked agonistic component for the presynaptic DA autoreceptors. Indeed, it caused a dose-related reduction in locomotor activity over a wide dose range and prolonged periods of observation without stimulating locomotor activity, reflecting postsynaptic DA receptor activation, even at the highest doses. Ro 41-9067 inhibited the gamma-butyrolactone-induced increase in I-dopa accumulation in the rat striatum, an effect sensitive to haloperiodol. Ro 41-9067 inhibited K(+)-induced [3H]DA release and significantly reduced the striatal contents of the DA metabolites, dihydroxyphenilacetic acid and homovanillic acid. Furthermore, the compound counteracted stereotyped behavior and locomotor stimulation induced by amphetamine. Finally, Ro 41-9067 did not appear to act on postsynaptic D2 receptors because it, similarly to B-HT 920 but differently from bromocriptine, quinpirole and lisuride, did not change basal or forskolin-stimulated adenylate cyclase activity. Only at very high concentrations Ro 41-9067 increased adenylate cyclase activity, this effect being due to a D1 agonistic component.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1993

Conformational aspects of the muscarinic receptor interactions of bicyclic isoxazole ester bioisosteres of arecoline.

3-Methoxy-4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridine (O-Me-THPO) and O,5-di-Me-THPO are conformationally restricted bioisosteres of the muscarinic agonists norarecoline and arecoline, respectively, showing partial agonist effects at muscarinic acetylcholine receptors. The 7-membered ring analogue of O-Me-THPO, 3-methoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (O-Me-THAO), shows higher affinity for muscarinic receptor sites than O-Me-THPO or O,5-di-Me-THPO. Similarly, O-Et-THAO binds much more tightly to muscarinic receptor sites than its 6-membered ring analogues, O-Et-THPO and O-Et-5-Me-THPO. Based on receptor binding data, O-Me-THPO and O-Me-THAO, and O-Et-THPO and O-Et-THAO, respectively, show similar degrees of partial agonism. They also show similar relative affinities for muscarinic M1 and M2 receptor sites. Using the semiempirical quantum mechanics programme, AM1, and the molecular mechanics programme, SYBYL, we have studied the conformational flexibility of the O-alkyl-THPO and O-alkyl-THAO ring systems. As expected, the 7-membered ring of the latter system was shown to be markedly more flexible than the piperidine rings of O-alkyl-THPO analogues. On the basis of this analysis, a common pharmacophore for these two classes of compounds was constructed.

Arecoline↗
PubMed1993

Autoradiographic mapping of M3 muscarinic receptors in the rat brain.

The regional distribution of putative M3 receptors was studied by quantitative autoradiography of rat brain sections labeled with 4-diphenylacetoxy-N-methyl-piperidine methioxide. The radioligand appears to label multiple muscarinic receptor subtypes in direct binding assays, as evidenced by competition experiments with unlabeled pirenzepine and 11-([2-[(2-(diethylamino)methyl]-1- piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodi azepine-6-on. Conditions favoring the selective labeling of M3 receptors were determined on the basis of the competition studies and were subsequently applied to regional mapping of M3 receptor binding. Under the conditions used, autoradiographic images may be obtained with both 9-fold M3-to-M1 selectivity and 12-fold M3-to-M2 selectivity. Although distributed widely at relatively low prevalence throughout the neuraxis, M3 receptors are apparently enriched relative to M1 and M2 receptors in several diencephalic and brain stem regions including thalamic and hypothalamic nuclei, the substantia nigra, superior colliculus, periaqueductal gray and the pons. The present results suggest that the binding of 4-diphenylacetoxy-N-methyl-piperidine methioxide, under appropriate conditions, may permit direct estimation of M3 receptors in mammalian brain.

Animals↗
PubMed1996

[Seroquel in a resistant schizophrenic with negative and positive symptoms].

Refractoriness to treatment is a common problem in management of schizophrenics. Conventional pharmacotherapy is usually effective in controlling positive symptoms of the disease, such as delusions and hallucinations. However, they have restricted ability to affect negative symptoms (flat affect, social withdrawal) and to reverse functional disability and behavioral deviance. Furthermore, typical neuroleptics produce adverse effects, such as extrapyramidal symptoms and tardive dyskinesia. A new generation of antipsychotic agents with a low profile of side-effects and good tolerance has recently been developed and actively investigated. Seroquel (ICI 204-636), a dibenzoth azepine derivative, is a novel, putative, potential, atypical neuroleptic; it is a combined dopamine/ serotonin receptor antagonist. We report a 54-year-old man suffering from chronic therapy-resistant schizophrenia, with both positive and negative symptoms, who was successfully treated with Seroquel during 1 year.

Antipsychotic Agents↗
PubMed1997

Characterization of the metabolites of carbamazepine in patient urine by liquid chromatography/mass spectrometry.

The urinary metabolites of carbamazepine (CBZ) in epileptic patients receiving long-term drug treatment have been characterized by LC/MS. CBZ-10,11-epoxide (9.6-15.0 micrograms/ml), trans-10, 11-dihydrodiol-CBZ (273.0-400.00 micrograms/ml), and CBZ (2.4-3.8 micrograms/ml) were measured by HPLC. The secondary N-glucuronide of CBZ, four phenolic O-glucuronides (including those of 2- and 3-OH-CBZ), two additional OH-CBZ O-glucuronides, and the N-glucuronide of CBZ-10,11-epoxide constituted the products of either direct conjugation or preliminary monoxygenation. Derivatives of these monoxygenated compounds, which were characterized as O-glucuronides, were represented by dihydroxylated (catechol) CBZ and its putative O-methyl metabolite and by 10,11-dihydrodiol-CBZ. 10,11-Dihydro-10-OH-CBZ O-glucuronide, a metabolite thought to be excreted only by uremic subjects, was not found. More complicated biotransformations of the 10,11-ene moiety were revealed by two carbinol products of azepine ring contraction: 9-OH-methyl-10-carbamoyl acridan and an hydroxylated derivative thereof, which were excreted as O-glucuronides. No polar sulfur-containing metabolites that might serve as indicators of reactive intermediate formation were found in human urine.

Adult↗
PubMed1998

Inhibition of voltage-dependent sodium channels by the anticonvulsant gamma-aminobutyric acid type A receptor modulator, 3-benzyl-3-ethyl-2-piperidinone.

3-Benzyl-3-ethyl-2-piperidinone (3-BEP) belongs to a family of compounds that includes alpha- substituted gamma-butyrolactones, gamma-thiobutyrolactones, 2-pyrrolidinones and hexahydro-2H-azepin-2-ones. Many of these drugs exhibit potent in vivo anticonvulsant activity in mice. Previous electrophysiological studies demonstrated that they potentiate gamma-aminobutyric acid- (GABA) mediated chloride currents. This GABAA receptor modulation was thought to be the main mechanism of anticonvulsant activity. We report that 3-BEP also modulates sodium channels. It decreased sodium currents in cultured rat hippocampal neurons in a voltage- and concentration-dependent manner. The drug's apparent affinity increased as neurons were depolarized. At a holding potential of -60 mV, the apparent IC50 was 487 microM. This concentration is comparable to its EC50 for GABAA modulation (575 microM). Current blockade occurred over all activation voltages tested. The steady state inactivation curve was shifted by 600 microM 3-BEP from V50 = -65.3 mV to -72.0 mV, and recovery from inactivation was slowed from tau = 4.9 to 12.8 msec. Sodium current inhibition was not observed for three related compounds, suggesting a degree of chemical specificity for this activity. We conclude that in addition to its known effects on GABAA receptors, 3-BEP modulates sodium channels. Therefore this compound may prevent seizures by both enhancing inhibition and diminishing neuronal excitability.

Animals↗