Antidiarrheal,vasorelaxant, and neuropharmacological actions of the diterpene tilifodiolide

Salvia tiliifolia is used in folk medicine as a relaxant agent and for the treatment of diarrhea and neurodegenerative diseases. Tilifodiolide (TFD) is a diterpene obtained from this plant. The purpose of this work was to evaluate the antidiarrheal, vasorelaxant, and neuropharmacological actions of TFD. These effects were selected based on the folk medicinal use of S. tiliifolia. The antidiarrheal activity of 1–50 mg/kg p.o. TFD was assessed with the castor oil related tests. The vasorelaxant effect of TFD (0.9–298 μM) was performed with smooth muscle tissues from rats, and its mechanism of action was evaluated using different inhibitors. The sedative, anxiolytic, and antidepressant effects of 1–100 mg/kg TFD were assessed. The possible mechanisms of action of the anxiolytic and antidepressant effects of TFD were evaluated using inhibitors. TFD exhibited antidiarrheal (ED₅₀ = 10.62 mg/kg) and vasorelaxant (EC₅₀ = 48 ± 3.51 μM) effects. The coadministration of TFD with N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), reverted the vasorelaxant action showed by TFD alone. TFD exerted anxiolytic actions (ED₅₀ = 20 mg/kg) in the cylinder exploratory test, whereas TFD (50 mg/kg) showed antidepressant actions in the tail suspension test by 44%. The pretreatment with 2 mg/kg flumazenil partially reverted the anxiolytic actions of TFD, whereas the pretreatment with 1 mg/kg yohimbine abolished the antidepressant effects of TFD. In summary, TFD exerted antidiarrheal activity by decreasing the intestinal fluid accumulation and vasorelaxant effects mediated by nitric oxide and cyclic guanosine monophosphate. TFD showed anxiolytic and antidepressant effects by the partial involvement of gamma-Aminobutyric acid (GABA) receptors and the possible participation of α2-adrenoreceptors, respectively.     

Zatosetron,a selective 5-HT3 receptor antagonist: Pharmacological activities of human and animal metabolites

Zatosetron is a potent, orally active 5-HT₃ receptor antagonist with a long duration of activity in laboratory animals and humans. Several metabolites have been detected in plasma and urine of humans and experimental animals receiving zatosetron. The present study was designed to explore the pharmacological activity of the detected metabolites, 3-hydroxyzatosetron, 3-ketozatosetron, and N-desmethylzatosetron, relative to the parent molecule. These three metabolites had relatively high affinity at 5-HT₃ receptors based on in vitro radioligand binding and inhibited serotonin-induced bradycardia in urethane-anesthetized rats after intravenous administration. However, these metabolites had lower affinity and were less potent than zatosetron. Of these metabolites, 3-hydroxyzatosetron (ED₅₀ = 4.0 μg/kg iv) was approximately 5-fold less potent than zatosetron (ED₅₀ = 0.8 μg/kg iv) in vivo and had approximately 10-fold lower affinity at 5-HT₃ receptors in vitro relative to zatosetron. N-desmethylzatosetron and 3-ketozatosetron were approximately 15-fold less potent than zatosetron in vivo as 5-HT₃ receptor antagonists. With regard to duration of activity in vivo, after intravenous administration, 3-hydroxyzatosetron and 3-ketozatosetron blocked 5-HT₃ receptors longer than zatosetron, whereas N-desmethylzatosetron showed a duration of pharmacological activity similar to zatosetron. A fourth metabolite, zatosetron-N-oxide can exist in two isomeric forms, with stereoselective N-oxidation of zatosetron resulting in formation of only one isomer in humans, zatosetron-β-N-oxide. Zatosetron-β-N-oxide had approximately 100-fold lower 5-HT₃ receptor affinity relative to zatosetron and was approximately 150-fold less active as an antagonist at 5-HT₃ receptors in vivo (ED₅₀ = 115 μg/kg iv). Thus, although pharmacological activity was observed with all four metabolites, they were all less active in vivo than zatosetron. Therefore, these metabolites would contribute significantly to the activity of zatosetron only if plasma (and tissue) levels greatly exceeded those of zatosetron. © 1993 Wiley-Liss, Inc.     

Anticonvulsant Profile of 4-Amino-(2-methyl-4-aminophenyl)benzamide in Mice and Rats

Abstract: An original ameltolide analogue 4-amino-(2-methyl-4-aminophcnyl)benzamide, in which a second amino group has been introduced, was synthesized and evaluated for anticonvulsant activity. After intraperitoneal administration to mice, 4-amino-(2-methyl-4-aminophenyl)benzamide was found active in the maximal electroshock seizure test and against the tonic seizures elicited either by bicuculline or 3-mercaptopropionic acid. 4-amino-(2-methyl-4-arainophenyl)benzamidc (4A-2M4A-PB) gave anti maximal electroshock seizures ED₅₀, of 63 umol/kg (15.4 mg/kg) and a TD₅₀ of 676 μmol/kg (163 mg/kg), yielding a PI of 10.7: the potency is similar to that of the 4-amino-(2-rnethyl-3-aminophenyl)phthalimide (4-A-2M3A-PP), superior to that of 4-amino-(2,6-dimethylphenyl)phlhaiimide (4A-2,6-DMPP), close to that of phenytoin and carbamazepine and inferior to that of ameltolide. 4A-2M4A-PB with an ED₅₀ of 41 [28-60] μmol/kg (9.9 mg/kg) is as active after oral administration to rats as carbamazepine, more active than ameltolide, 4-A-2M3A-PP and phenytoin and slightly less active than the 4A-2,6-DMPP. The introduction of a second amino group on the substituted phenyl ring does not affect drastically the anticonvulsant potency after intraperitoneal administration to mice; moreover, it seems to enhance the activity after oral administration. 4A-2M4A-PB is a good candidate both for further pharmacokinetic studies and for the study of the precise mechanism of action.     

Biochemical and pharmacological characterization of the putative dopamine autoreceptor agonist benzopyranopyridine,CGS 15873A

The substituted benzopyranopyridine, CGS 15873A (± trans-1,3,4,4a,4,10b-hexahydro-4-propyl-2H-[1]benzopyrano[3,4-b]-pyridine-70olmonohydrochloride), was evaluated for its dopamine receptor agonist and other properties in biochemical and behavioral test procedures. In the γ-butyrolactone (GBL) model of dopamine autoreceptor function, CGS 15873A i.p. had an ED₅₀ value of 1.83 m?mole/kg indicating that the compound had dopamine autoreceptor agonist activity. The corresponding p.o. value was 2.11 m?mole/kg, indicating reasonable oral bioavailability. The compound exhibited a shallow competition curve in displacing [³H] ADTN from dopamine recognition sites in a biphasic manner with IC₅₀ values of 6 and 234 nM, respectively. At the dopamine D₂ receptor defined by [³H] spiperone binding, CGS 15873A had an IC₅₀ value of 234 nM. The compound had negligible activity (IC₅₀ > 1 m?M) in binding assays for dopamine D₁, serotonin (5HT_1A, 5HT_1B, 5HT₂), and α₁-adrenergic binding sites. Moderate activity was, however, observed in α₂-adrenoceptor binding (IC₅₀ = 77 nM). CGS 15873A had a weak effect on stereotyped behavior (ED₅₀ > 106 μmole/kg i.p.), an indication of postsynaptic activity, but showed partial generalization in a clonidine discrimination paradigm, indicating that it was a partiall α₂ agonist. CGs 15873A appears to be a relatively selective dopmine agonist with preferentia activity at presynaptic autoreceptors and, as such, may represent a novel agent for treatment of disorders such as schizophreniaand Parkinsonism.     

Comparison of the specificity of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine and chlorimipramine as amine uptake inhibitors in mice

The ability of 3-(p-triflouromethylphenoxy)-N-methyl-3-phenylpropylamine amine hydrochloride (Lilly 110140) and chlorimipramine to block uptake into serotoninergic and noradrenergic neurons was determined by their antagonism of serotonin depletion in brain by p-chloroamphetamine and norephrine depletion in heart by 6-hydroxydopamine, respectively. Lilly 110140 blocked serotonin depletion with an ED₅₀ of 0.4 mg/kg and had no effect on norepinephrine depletion at doses up to 32 mg/kg. Chlorimipramine antagonized both serotonin depletion and norepinephrine depletion with ED₅₀ values of 10 and 6 mg/kg, respectively.     

Antinociceptive effects of a novel dual cyclooxygenase/5-lipoxygenase inhibitor (tepoxalin) and its primary (carboxylic acid) metabolite (RWJ 20142) in acute tests in mice and rats

Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED₅₀ value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED₅₀ = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED₅₀ = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED₅₀ = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED₅₀ = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to tepoxalin-induced antinociception. The inactivity of tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both tepoxalin and its primary metabolite contribute to tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.     

Biochemical and pharmacologic properties of 2614W94, a reversible,competitive inhibitor of monoamine oxidase-A

2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a selective, reversible inhibitor of monoamine oxidase-A with a competitive mechanism of inhibition and a K_i value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED₅₀ value after single oral dosing was 1.7 mg/kg, similar to an ED₅₀ value of 1.1 mg/kg estimated in the 5-hydroxytryptophan potentiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was observed by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal with a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37°C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepinephrine, and dopamine were clearly elevated in brains of rats after single oral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, an MAO-A selective inhibitor that has not been associated with problems relating to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibitors known and that they may have therapeutic potential as safe new antidepressant/anxiolytic agents. Drug Dev. Res. 45:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists

Histamine has been converted into a non-imidazole H₃-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N^α-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a K_i = 1.3 μM as an H₃ antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (K_i = 0.18 ± 0.10 μM, for [³H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO₂ into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (K_i = 39 ± 11 nM), ED₅₀ = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.     

Anti-inflammatory and diuretic effects of the diterpene ent-dihydrotucumanoic acid

Gymnosperma glutinosum (Spreng) Less (Asteraceae) is a shrub used in traditional medicine for the treatment of inflammatory and renal diseases. The ent-dihydrotucumanoic acid (DTA) is a diterpene obtained from G. glutinosum. This study evaluated the antioxidant, genotoxic, and diuretic properties of DTA, as well as its in vitro and in vivo anti-inflammatory actions. The antioxidant actions of DTA were assessed with the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2,2′-diphenyl-1-picrylhydrazyl (DPPH) assays, the genotoxic action was assessed with the comet assay, and the diuretic effects of DTA were assessed using metabolic cages. The anti-inflammatory actions were evaluated using primary murine peritoneal macrophages stimulated with LPS and the λ-carrageenan-induced hind paw edema test. DTA lacked antioxidant (IC₅₀ > 25,000 μg/mL) activity in the ABTS, FRAP, and DPPH assays. DTA at 500–1,000 μg/mL showed moderate genotoxicity. In LPS-stimulated macrophages, DTA showed IC₅₀ values of 74.85 μg/mL (TNF-α) and 58.12 μg/mL (NO), whereas the maximum inhibition of IL-6 (24%) and IL-1β (36%) was recorded at 200 μg/mL. DTA induced in vivo anti-inflammatory effects with ED₅₀ = 124.3 mg/kg. The in vitro anti-inflammatory activity of DTA seems to be associated with the decrease in the release of TNF-α and NO. DTA promoted the excretion of urine (ED₅₀ = 86.9 mg/kg), Na⁺ (ED₅₀ = 66.7 mg/kg), and K⁺ (ED₅₀ = 8.6 mg/kg). The coadministration of DTA with L-NAME decreased the urinary excretion shown by DTA alone. Therefore, the diuretic activity is probably associated with the participation of nitric oxide synthase. In conclusion, DTA exerted anti-inflammatory and diuretic effects, but lacked antioxidant effects.     

Effects of the antidepressant compound nefazodone on central monoaminergic neuronal discharge in rats

The effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single-unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED₂₅ = 1.953 mg/kg). This may in part be caused by the 5-HT₂ antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED₅₀ = 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED₂₅ for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED₅₀ = 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nefazodone.     

Biochemical evidence for the involvement of central serotonergic neurotransmission in the action of the antidepressant drug Medifoxamine

Medifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5-HT_1c and 5-HT₂ receptor subtypes and to 5-HT uptake sites (IC₅₀ 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5-HT₂ receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [³H]-5-HT uptake and a dose-dependent down-regulation of 5-HT₂ receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5-HT₂ receptors, which could contribute to its antidepressant effect.     

Structure-based design,synthesis, and anticonvulsant activity of isatin-1-N-phenylacetamide derivatives

In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1-yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED₅₀ of 91.3 mg/kg, TD₅₀ of >1,000 mg/kg, a higher protective index (PI = TD₅₀/ED₅₀, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.     

Note:Cytotoxic Activities of N-Acyllolines

Abstract

N-Acylloline derivatives were synthesized from loline (hexahydro-N-methyl-2,4-methano-4H-furo[3,2-b]pyrrol-3-amine) and tested for lethality to brine shrimp and for cytotoxicities to three human solid tumor cell lines. N-Acyl derivatives of loline having chain lengths of 12 to 18 carbons showed significant (mean ED₅₀ of 0.274 μg/ml) cytotoxicities in A-549 human lung carcinoma, MCF-7 human breast carcinoma and HT-29 human colon adenocarcinoma. Brine shrimp lethality test data paralleled the solid tumor cytotoxicity test data.     

The pharmacology of ketanserin,the first selective serotonin S2-antagonist

The quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5-HT): 0.15 mg/kg (ED₅₀ s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine-induced cyanosis in rats (ED₅₀ s.c., 0.056 mg/kg), inhibition of mescaline-induced head twitches in rats (ED₅₀ s.c., 0.097 mg/kg), and inhibition of 5-HT-induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5-HT-antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α-adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S₂-receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (K_i = 0.39 nM), and affinity of drugs for S₂-receptors highly correlated with their activity against serotonin-induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A₂-value of ketanserin: 0.83 nM) and serotonin-induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! -binding, of agonist activity on vascular smooth muscle, of inhibition of 5-HT uptake into platelets, and of 5-HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin-antagonists. On the basis of this profile of pure and selective serotonin S₂-antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long-standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S₂-receptors as the primary pathological mediator of vascular congestion.     

The effect of N-substituted alkyl groups on the anticonvulsant activities ofN-Cbz-α-amino-N-alkylsuccinimides

For the purpose of defining the effects of theN-substituted alkyl groups on the anticonvulsant activities ofN-Cbz-α-aminosuccinimides, various (R)-and(S)-N-alkyl substitutedN-Cbz-α-aminosuccinimides (1 and2) were prepared from the corresponding (R)-and(S)-N-Cbz-aspartic acid by using known reaction and were evaluated the anticonvulsant activies in the MES and PTZ tests, including their neurotoxicities. The most active compound in the MES test was(R)-N-Cbz-α-amino-N-methylsuccinimide (1b) (ED₅₀=52.5 mg/kg, Pl-3.2). And in case of the PTZ test,(R)-N-Cbz-α-amino-N-ethylsuccinimide (1c) was the most active compound (ED₅₀=32.5 mg/kg, Pl=3.1). The order of anticonvulsant activities of these compounds against the MES test, as judged from the ED₅₀ values for theR series (1), wasN-methyl >N-isobutyl > non-substituted >N-ethyl,N-allyl >N-benzyl compound; for theS series (2)N-methyl >N-allyl > non-substituted >N-isobutyl >N-ethyl >N-benzyl compound. The anticonvulsant activities in the PTZ tests of these compounds exhibited somewhat different pattern; for theR series (1)N-ethyl >N-methyl >N-isobutyl> non-substituted >N-allyl >N-benzyl compound in order of decreasing activity; forS series (2)N-ethyl >N-allyl, non-substituted >N-isobutyl >N-methyl >N-benzyl compound in order of decreasing activity.     

Inhibition by antiarrhythmic and β-sympatholytic drugs of serotonin uptake by human platelets: Experimentsin vitro andin vivo

Summary The effects of prenylamine, verapamil, propranolol, INPEA, and pindolol on the uptake of serotonin by human platelets were investigatedin vitro andin vivo. Serotonin uptakein vitro was diminished by these drugs. Their order of potency, according to IC 50 values estimated from the dose response curves was: propranolol > prenylamine > verapamil > INPEA > pindolol. The inhibitory activity of these drugsin vivo was also studied by measuring serotonin uptake by platelets isolated 90 min after oral administration to healthy volunteers of 10 µmoles of propranolol, INPEA and prenylamine, all approximately 3 mg/kg; verapamil, approximately 5 mg/kg; and 2 µmoles/kg (0.5 mg/kg) of pindolol. In agreement with the degree of inhibition observedin vitro, propranolol was more effective than verapamil and INPEA, and, as predicted from thein vitro experiments, pindolol showed no measurable membrane activity. Prenylamine, an effective inhibitor of serotonin uptake by human plateletsin vitro, was activein vivo only after repeated oral doses of 10 µmoles/kg. It is concluded that measurement of the uptake of serotonin by human platelets is a sensitive method for investigating non-specific effects of drugs on membrane functionsin vivo as well asin vitro.Supported by a grant from the Deutsche Forschungsgemeinschaft.A preliminary report of this work has been presented at the 12. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft, Mainz 1971 (Grobeckeret al., 1971).     

SL 81.0385: A novel selective and potent serotonin uptake inhibitor

SL 81.0385 (4-[(2-naphthalenyl)methoxy]piperidine) is a potent competitive inhibitor of serotonin uptake into rat hypothalamic synaptosomes and human platelets (IC₅₀ values of 18 and 13 nM, respectively), which exhibits a high selectivity for inhibiting serotonin uptake relative to noradrenaline or dopamine uptake in vitro. SL 81.0385 also exhibits potent serotonin uptake inhibiting properties in vivo as demonstrated by its ability to antagonize the p-chloroamphetamine-induced depletion of rat cerebral serotonin levels (ED₅₀ = 2.5 mg/kg i.p.). Similarly, SL 81.0385 is a potent inhibitor of ³H-imipramine and ³H-paroxetine binding to the serotonin transporter complex in rat cortical membranes (Ki values of 0.5 and 3.2 nM, respectively), but it exhibits a much lesser affinity for radioligand binding to the noradrenaline, adrenaline, and dopamine transporters. The selectivity of SL 81.0385 for serotonergic systems is also demonstrated by its effects on cerebral monoamine metabolism. Indeed, SL 81.0385 decreases, ex vivo, endogenous 5-hydroxyindoleacetic acid (5-HIAA) levels in the rat striatum, and, in vivo, extracellular 5-HIAA concentrations (as measured by differential pulse voltammetry) in the rat cerebral cortex. In contrast, SL 81.0385 fails to decrease striatal levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid and hypothalamic levels of total, 3,4-dihydroxyphenylethyleneglycol. SL 81.0385 is devoid of inhibitory activity toward monoamine oxidase and has no affinity for cerebral muscarinic, H₁ histaminergic, α₁-, α₂-, and β-adrenergic, D₂ dopaminergic, and benzodiazepine receptors, and it possesses only weak affinity for 5-HT₂ receptors. The present results indicate that SL 81.0385 is a highly potent and selective inhibitor of serotonin uptake, chemically unrelated to the tricyclics, and it should find application in the treatment of depression, obesity, and alcoholism.     

(2E,4E)-N-(4-(1H-Indol-3-yl)piperidin-1-yl)alkyl-5-(substituted phenyl)-2,4-pentadienamides as Antiallergic Agents with Antihistaminic and Anti Slow-Reacting Substance (SRS) Activities

As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow-reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4–20. Testing for in vivo antianaphylactic activity and for in vitro anti-SRS activity revealed that (2E,4E)-5-(3,5-dimethoxy-4-hydroxyphenyl)-N-(2-(4-(1H-indol-3-yl)piperidin-1-yl)ethyl)-2,4-pentadienamide ( 11 ) exhibited potent dual activities with ED₅₀ = 0.89 mg/kg and IC₅₀ = 1.43 μM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate.