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PubMed1992

Antagonistic activity of Y-25130 on 5-HT3 receptors.

This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dih yd ro- 2H-1,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 microM) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, alpha 1-adrenoceptor, alpha 2-adrenoceptor, muscarine and benzodiazepine) even at a 10 microM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.

Acetylcholine↗

PubMed1991

Electrophysiological actions of BRB-I-28 in canine myocardial tissues.

To obtain a better understanding of the possible electrophysiological bases of the antiarrhythmic actions of 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate (BRB-I-28), microelectrode recordings of myocardial electrical activity were obtained in canine Purkinje and ventricular tissue, and in isolated canine ventricular myocytes. BRB-I-28 (1.0 and 3.2 mg/l) reduced Vmax, action potential amplitude, overshoot potential and conduction velocity in Purkinje tissues without altering action potential duration or spontaneous automaticity. Vmax and conduction velocity were reduced only at paced cycle lengths of 500 msec or less. BRB-I-28 (3.2 and 10 mg/l) also reduced Vmax, action potential amplitude and overshoot potential in subendocardial and epicardial ventricular muscle, with Vmax reduced only at cycle lengths of 500 msec or less. Recovery half-times for Vmax estimated in canine subendocardium were 330 +/- 28 and 336 +/- 25 msec at BRB-I-28 concentrations of 3.2 and 10 mg/l, respectively. In epicardium, conduction velocity longitudinal to fiber orientation was depressed more than conduction velocity transverse to fiber orientation, despite similar changes in Vmax. In both epicardial and subendocardial ventricular muscle, a reduction in Vmax is observed in the absence of alterations in action potential duration. Experiments using myocytes isolated from canine epicardial tissue demonstrated similar rate-dependent changes in Vmax as ventricular epicardium. The data demonstrate a rate-dependent depression of Vmax by BRB-I-28 in canine ventricular tissues. The depression of conduction occurs only at rapid paced rates and occurs in the absence of changes in Purkinje cell automaticity or action potential duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1994

Effects of 5-HT3 receptor antagonists on binding and function of mouse and human GABAA receptors.

Both 5-HT3 receptor antagonists and benzodiazepine receptor ligands have effects on anxiety, and alter the behavioral action of ethanol. For these reasons, we tested the ability of several 5-HT3 receptor antagonists to inhibit the ligand binding and function of the gamma-aminobutyric acidA/benzodiazepine receptor Cl- channel complex of mouse brain membranes. MDL 72222 (1-a-H-3-a-5-aH-optropan-3yl-3,5-dichlorobenzoate) and LY 278584 (1-methyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-1H-indazole-3- carboxamide) inhibited [3H]flunitrazepam binding with Ki values of approximately 20 microM; ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) was more potent with a Ki of 0.8 microM. ICS 205-930 (50 microM) had no effect on [3H]muscimol binding. ICS 205-930, MDL 72222, and LY 278584 all inhibited the binding of [35S]TBPS (tert-butylbicyclophosphorothionate) with Ki values of approximately 10 microM and reduced muscimol-dependent 36Cl- flux into mouse cortical microsacs by 30-45% at a concentration of 10 microM. ICS 205-930, MDL 72222, and LY 278584 (at micromolar concentrations) reduced GABA-gated chloride currents studied in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2S GABAA receptor subunits. ICS 205-930 differed from the other two 5-HT3 receptor antagonists in that it induced a biphasic effect on GABA-gated currents: at concentrations from 0.1 to 5 microM it potentiated GABA responses, whereas at higher concentrations (50-100 microM) it produced inhibition. The stimulatory action induced by ICS 205-930 was due to interaction at the benzodiazepine recognition site because expression of the gamma 2 subunit was required and Ro 15-1788 (1 microM) completely prevented the potentiation caused by ICS 205-930. Thus, several 5-HT3 receptor antagonists inhibit benzodiazepine binding and affect GABAA receptor function. These actions are most pronounced for ICS 205-930 and likely involve direct affects on the GABA/benzodiazepine complex rather than interactions with 5-HT3 receptors.

Animals↗

PubMed1993

Effects on general behaviour and neurotransmitter functions of a new 5-hydroxytryptamine3 receptor antagonist with potential therapeutic relevance in central nervous system disturbances.

1. The general pharmacology of DAU 6215 (N-(endo-8-methyl-8-azabicyclo(3.2.1) oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride, CAS 127618-28-4), a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was investigated for a preliminary evaluation of its toxicity and possible side-effects related to interferences with neurotransmitter functions. 2. In vitro studies--receptor binding: DAU 6215 showed a high affinity for 5-HT3 receptors (Ki, nmol/l: 3.8) without any significant affinity for other serotonergic, adrenergic or dopaminergic receptors. A certain affinity was found for muscarinic (M) receptors (Ki, nmol/l: M1 = 95; M2 = 6,917; M3 = 181). 3. In vivo studies--general behaviour: In mice, DAU 6215 was well tolerated up to 100 mg/kg p.o. and 30 mg/kg i.v. The only noticeable symptom was mydriasis. No other major symptoms appeared up to the maximum non lethal doses (100 mg/kg p.o. and 30 mg/kg i.v.). At lethal doses, deaths occurred with signs of central nervous system excitation, like tremors, twitches and convulsions. Survived mice exhibited a complete recovery from symptoms within 1 h from administration. DAU 6215 did not exhibit any effect either on motor and exploratory activity or in the traction test in mice up to 30 mg/kg i.p. In the open field test in rats, DAU 6215 (0.01 and 10 mg/kg p.o.) failed to modify the behavioural parameters considered, with the exception of a decrease in defecations at 10 mg/kg. 4. In vivo studies--neurotransmitter functions: a) Monoaminergic transmission: reserpine-induced hypothermia in mice was not antagonized by DAU 6215 (0.01-1 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Pharmacological analyses of endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H- benzimidazole-1-carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat esophagus and ileum of guinea pig: role of endogenous 5-hydroxytryptamine.

Functional estimates of affinity for endo-6-methoxy-8-methyl-8- azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxyla te hydrochloride (DAU 6285) were made at the 5-hydroxytryptamine4 (5-HT4) receptor in isolated preparations of rat esophageal tunica muscularis mucosae (TMM) and guinea pig ileum. In the TMM, relaxation of carbachol-induced contracture by 5-HT4 receptor agonism of longitudinal muscle was recorded. Estimated pA2 values for DAU 6285 of 6.9 to 7.2 were tissue, time (1-3 hr equilibration) and agonist-independent. However, DAU 6285 increased the maximal response to 5-HT and 5-methoxytryptamine in the TMM and augmented the contractile tone to carbachol. These effects were not observed in guinea pig ileum, suggesting a tissue-dependent mechanism. [3a-Tropanyl]-1H-indole-3-carboxylic acid ester (tropisetron) and 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205-557), two other 5-HT4 receptor antagonists, mimicked the effects of DAU 6285. Mechanistic experiments suggest agonism by endogenous 5-HT, within the isolated TMM, to explain the effects of 5-HT4 receptor antagonists. Pretreatment of rats with parachlorophenylalanine to deplete endogenous 5-HT, prevented the effect of DAU 6285 on the maximal response to 5-HT and carbachol-induced tone. In conclusion, DAU 6285 acts as a silent, competitive antagonist at 5-HT4 receptors in rat TMM and guinea pig ileum. However, in the TMM, endogenously released 5-HT confounds interpretation. The TMM, as a quantitative assay system for 5-HT4 receptor agonists and antagonists may be improved by pretreating rats with parachlorophenylalanine.

Animals↗

PubMed1984

Pharmacokinetics and biotransformation of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498) in rat, dog and man.

After oral administration, 2 mg/kg in rat and dog, 10 mg in man, of the carbon-14-labeled angiotensin I converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498), absorption (rat 56%, dog 43%, man 56%) occurred rapidly and induced maximum blood levels between 0.25 and 1 h. The radioactivity disappeared from the blood in one or two phases with half-lives of 0.6 h in the rat, 1/3.8 h in dog and 0.5/2.9 h in man. Studies in rats have shown that the radioactivity is distributed rapidly to all tissues. Markedly higher concentrations than in the blood were found in the liver, kidneys, and particularly in the lungs. The elimination from the lungs, which showed the highest concentrations until 5 d after administration, occurred with a half-life of 63 h. In rats, 26% of the dose was excreted with the urine and 71% with the feces. About one third of the dose was eliminated with the bile and about 13% was reabsorbed from the bile. The excretion in the breast milk of rats was low. Placental transfer in pregnant rats was low and transient. The radioactivity recovered from the urine of dogs amounted to 15%, that recovered from the feces amounted to 79%. In man, 56% of the radioactivity was excreted with the urine and less than 40% with the feces. Whereas in rat urine one metabolite dominates, the metabolite patterns in urine and serum/plasma of man and dog - which are very much alike - reveal a different biotransformation with three main metabolites. Unchanged Hoe 498, as well as its dicarboxylic acid and other metabolites appear only in low concentrations in this pattern.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Membrane receptors involved in modulation of responses of spinal dorsal horn interneurons evoked by feline group II muscle afferents.

Modulatory actions of a metabotropic 5-HT1A&7 membrane receptor agonist and antagonist [(+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin; N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide] and an ionotropic 5-HT3 membrane receptor agonist and antagonist [2-methyl-serotonin (2-Me 5-HT); N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride] were investigated on dorsal horn interneurons mediating reflex actions of group II muscle afferents. All drugs were applied ionophoretically in deeply anesthetized cats. Effects of agonists were tested on extracellularly recorded responses of individual interneurons evoked by electrical stimulation of group II afferents in a muscle nerve. Effects of antagonists were tested against the depression of these responses after stimulation of raphe nuclei. The results show that both 5-HT1A&7 and 5-HT3 membrane receptors are involved in counteracting the activation of dorsal horn interneurons by group II afferents. Because only quantitative differences were found within the sample of the tested neurons, these results suggest that modulatory actions of 5-HT on excitatory and inhibitory interneurons might be similar. The relationship between 5-HT axons and axons immunoreactive for the 5-HT3A receptor subunit, which contact dorsal horn interneurons, was analyzed using immunofluorescence and confocal microscopy. Contacts from both types of axons were found on all interneurons, but their distribution and density varied, and there was no obvious relationship between them. In two of six interneurons, 5-HT3A-immunoreactive axons formed ring-like arrangements around the cell bodies. In previous studies, axons possessing 5-HT3 receptors were found to be excitatory, and as 2-Me 5-HT depressed transmission to dorsal horn interneurons, the results indicate that 5-HT operates at 5-HT3 receptors presynaptic to these neurons to depress excitatory transmission.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Biological properties of the benzodiazepine amidine derivative L-740,093, a cholecystokinin-B/gastrin receptor antagonist with high affinity in vitro and high potency in vivo.

A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidines), which contain a cationic solubilizing group and which are antagonists for the cholecystokinin (CCK)-B receptor, have been identified. Optimization of this series led to the identification of an azabicyclononane amidine, L-740,093 [N-[(3R)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1-methyl-2- oxo- 1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea], that bound with high affinity of CCK-B receptors from guinea pig cerebral cortex (IC50 of 0.1 nM) and had a CCK-B/CCK-A receptor selectivity of 16,000. In comparison, L-365,260 had 85-fold lower affinity (8.5 nM) and was only 87-fold selective for CCK-B over CCK-A receptors. L-740,093 bound with high affinity to guinea pig gastrin receptors in vitro (IC50 of 0.04 nM). Electrophysiological studies on slices of rat ventromedial hypothalamic nucleus showed that L-740,093 produced rightward shifts of the concentration-response curve for the CCK-B receptor agonist pentagastrin (Kb of 0.06 nM). L-740,093 blocked pentagastrin-induced gastric acid secretion in anesthetized rats with a 50% inhibitory dose of 0.01 mg/kg, intraperitoneally, showing 100-fold greater activity, compared with L-365,260 (50% inhibitory dose of 1 mg/kg, intraperitoneally). An ex vivo binding assay in mice was used to investigate the interaction of L-740,093 with central CCK binding sites. After intravenous administration, L-740,093 inhibited ex vivo binding dose dependently, with a 50% effective dose of 0.2 mg/kg. These studies demonstrate that L-740,093 is the most potent and selective CCK-B antagonist yet described and that it has excellent central nervous system penetration.

Animals↗

PubMed1993

Pharmacological characterization of the novel cholinomimetic L-689,660 at cloned and native brain muscarinic receptors.

1-Azabicyclo[2,2,2]octane,3-(6-chloropyrazinyl)maleate (L-689,660) reportedly is an agonist with selectivity for M1 and M3 muscarinic receptors. We confirmed this in functional assays of brain muscarinic receptors and of cloned human muscarinic receptors transfected into Chinese hamster ovary (CHO-K1) cells. For stimulation of phosphoinositide turnover in rat cortical and hippocampal dissociated tissue, L-689,660 was a partial agonist (24% and 26% intrinsic activity, respectively, relative to oxotremorine-M) with EC50 values of 71 microM and 118 microM, respectively. At putative M4 receptors coupled to cyclic AMP inhibition in rat striatum, however, L-689,660 acted as a competitive antagonist (KB = 0.4 microM). Furthermore, at putative M2/M4 autoreceptors that regulate acetylcholine release in the hippocampus, the drug also behaved as an antagonist (KB = 2.1 microM). These data indicated that L-689,660 behaves as a postsynaptic agonist/presynaptic antagonist at central cholinergic synapses. Further aspects of the selectivity of the drug for specific muscarinic receptor subtypes were revealed with phosphoinositide turnover assays of cloned muscarinic receptors expressed in CHO-K1 cells. L-689,660 was a partial agonist at transfected hm1 and hm3 receptors and was more potent than oxotremorine-M; however, the drug was inactive at transfected hm5 receptors. Partial agonist activity at hm1 and hm3 muscarinic receptors was present even after using alkylation to reduce receptor numbers to levels comparable to that level found in the hm5 cell line. Thus, with functional assays either with brain tissue or with transfected cell lines, L-689,660 was shown to be an agonist for the M1 and M3 receptors but not for M5 or M4 receptors.

Acetylcholine↗

PubMed2000

Effects of CI-1002 and CI-1017 on spontaneous synaptic activity and on the nicotinic acetylcholine receptor of Torpedo electric organ.

The effect of azepino[2,1-b]quinazoline 1,3-dichloro-6,7,8,9,10, 12-hexahydro-, mono-hydrochloride (CI-1002), a tacrine derivative, and 1-azabicyclo[2.2.1]heptan-3-one, O-[3-(methoxyphenyl)-2-propynyl]oxime [R-(Z)]-2-butenedioate (CI-1017), a muscarinic M(1) receptor agonist, on spontaneous synaptic activity was investigated by measuring amplitude, rise time, velocity of rising, half-width, and electrical charge of miniature endplate potentials (m.e.p.p.) recorded extracellularly in Torpedo electric organ fragments. The effect of CI-1002 and CI-1017 on the nicotinic acetylcholine receptor was investigated by measuring the current induced by acetylcholine in Xenopus laevis oocytes transplanted with membranes from Torpedo electric organ. CI-1002, at a concentration of 1 microM, altered the m.e.p.p. by increasing the amplitude (from 1.08+/-0.01 to 2.76+/-0.03 mV), rise time (from 0. 700+/-0.006 to 1.02+/-0.01 ms), rising rate (from 1.79+/-0.02 to 3. 45+/-0.05 mV/ms), half-width (from 0.990+/-0.008 to 2.40+/-0.02 ms), and electrical charge (from 304+/-4 to 784+/-11 mV s). CI-1017, at a concentration of 1 microM, altered the m.e.p.p. by decreasing the amplitude (from 1.08+/-0.01 to 0.650+/-0.007 mV), rise time (from 0. 700+/-0.006 to 0.530+/-0.007 ms), rising rate (from 1.79+/-0.02 to 1. 53+/-0.02 mV/ms), half-width (from 0.990+/-0.008 to 0.670+/-0.007 ms), and electrical charge (from 304+/-4 to 75+/-1 mV s). CI-1002 inhibited the acetylcholine-induced current of nicotinic acetylcholine receptors with an IC(50) of 3.4+/-0.3 microM. CI-1017 inhibited the acetylcholine-induced current of nicotinic acetylcholine receptors with an IC(50) of 0.8+/-0.1 microM. These results indicate that, although both drugs interacted negatively with nicotinic acetylcholine receptors, CI-1002 overcame this inhibition by recruiting more acetylcholine to build a quantum.

Animals↗

PubMed1987

Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924.

The mechanisms by which BRL 24924 ([(+/-)- (endo)])-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo-[3.3.1]-non- 4-yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5-hydroxytryptamine (5-HT) receptors have been studied. In guinea-pig isolated ileum, BRL 24924 (10(-14)-10(-6) M) increased electrically-evoked, cholinergically-mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5-HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205-930. The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5-HT receptor which differs from those 5-HT M-receptors antagonized by ICS 205-930 or by higher concentrations of BRL 24924 in other test systems. BRL 24924 antagonized 5-HT-evoked, cholinergically-mediated contractions of guinea-pig isolated ileum (pA2 = 7.56 +/- 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1-10 nM reduced the tachycardia evoked by 5-HT. In anaesthetized rats, BRL 24924 0.3-83 nmol kg-1 i.v. antagonized the Bezold-Jarisch reflex evoked by 5-HT; the ID50 for BRL 24924 was 10.2 +/- 3.0 nmol kg-1 (3.7 +/- 1.1 microgram kg-1). A direct action of BRL 24924 on nerve function was excluded. In rat cortex, BRL 24924 10(-6) M did not displace [3H]-5-HT or [3H]-ketanserin binding to 5-HT1 and 5-HT2 receptors. The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5-HT M-receptor antagonist.

Animals↗

PubMed1993

BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties.

The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 microgram/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 microM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Comparative pharmacology of epibatidine: a potent agonist for neuronal nicotinic acetylcholine receptors.

Pharmacological properties of the (+)- and (-)-isomers of synthetic epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane, were compared with nicotine and acetylcholine on several subtypes of chicken and human nicotinic acetylcholine receptors (AChRs). Both isomers of epibatidine behaved as extremely potent full agonists on chicken (alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, alpha 7, and alpha 8) and human (alpha 3 beta 2, alpha 3 beta 4, and alpha 7) neuronal AChRs expressed in Xenopus oocytes. Currents induced by epibatidine were effectively blocked by the nicotinic antagonists hexamethonium and mecamylamine. Apparent affinity was 100 to 1000-fold higher for epibatidine than for nicotine or acetylcholine. EC50 values ranged from 1 nM (for homomeric chicken alpha 8) to 2 microM (for homomeric chicken alpha 7). Epibatidine showed comparatively lower affinity for muscle-type AChRs from Torpedo and humans (EC50 values, 1.6 and 16 microM respectively). In binding assays, epibatidine was used on AChR subtypes immunoisolated from chicken brain and retina (alpha 4 beta 2, alpha 7, and alpha 8), the human neuronal cell line SH-SY5Y (alpha 3 and alpha 7), Torpedo electric organ (alpha 1 beta 1 gamma delta), or the human rhabdomyosarcoma cell line TE671 (alpha 1 beta 1 gamma delta). Both isomers of epibatidine exhibited extremely high affinity for all neuronal AChRs tested, with KI values ranging from 0.6 pM (human alpha 3 AChRs) to 0.6 microM (chicken alpha 7 AChRs). In contrast, epibatidine had lower affinity for Torpedo muscle-type AChRs (KI approximately 5 microM). Racemic [3H]epibatidine was an effective labeling reagent for human alpha 3 beta 2 AChRs, exhibiting a KD (0.14 nM) similar to the KI values observed for unlabeled (+)-epibatidine (0.23 nM) or (-)-epibatidine (0.16 nM).

Animals↗

PubMed1998

Expression of fos protein in rat brain following administration of a nicotinic acetylcholine receptor agonist epibatidine.

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D1 and D2 receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 microgram/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D1 receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5. 0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 microgram/kg). Pretreatment with sulpiride, a dopamine D2 receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D1 receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D2 receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.

Animals↗

PubMed1997

Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central processes, such as learning and memory and analgesia. These receptors also mediate the reinforcing properties of nicotine in tobacco products and are increased in postmortem samples of brains of smokers. On the other hand, brains of individuals who have died from dementia of the Alzheimer type show abnormally low densities of nAChRs. In this study, the distribution and kinetics of [(+/-)-exo-2-(2-[18F] fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (18F-FPH), a high-affinity nAChR agonist, was evaluated in a baboon using PET. METHODS: After intravenous injection of 5 mCi [185 MBq] 18F-FPH into a 25-kg anesthetized baboon, sequential quantitative tomographic data were acquired over a period of 150 min. Regions of interest were placed and time-activity curves were generated. Brain kinetics of the radiotracer were calculated, and the in vivo regional binding in the baboon brain was compared with the known in vitro regional distribution of nAChRs in the rat and human brain. RESULTS: Brain activity reached a plateau within 60 min after injection of the tracer, and the binding was reversible. Elimination of 18F-FPH was relatively rapid from the cerebellum (clearance t[1/2] = 3 hr), intermediate from the hypothalamus/midbrain (t[1/2] = 7 hr) and slow from the thalamus (t[1/2] = 16 hr). Radioactivity due to 18F-FPH at 130 min postinjection was highest in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in the cerebellum. Subcutaneous injection of 1 mg/kg cytisine 45 min after injection of the radiotracer reduced brain activity at 130 min by 67%, 64%, 56% and 52% of control values in the thalamus, hypothalamus/midbrain, hippocampus and cerebellum, respectively. The regional binding of 18F-FPH at 130 min was highly correlated with the known densities of nAChR measured in vitro in human (r = 0.81) and rat brain (r = 0.90). CONCLUSION: These results demonstrate the feasibility of imaging nAChRs in vivo. Fluorine-18-FPH appears to be a suitable tracer to study nAChRs in the human brain.

Animals↗

PubMed2000

Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide.

In long-term clinical studies the beneficial effects of gliclazide on platelets have been related to a reduction in oxidative stress. This property is because of gliclazide's free radical scavenging ability that relates to the unique amino azabicyclo-octare ring, which is grafted on to the sulfonylurea. During a blinded clinical trial, the possible effects of gliclazide were assessed in 30 non-insulin-dependent diabetic patients. All patients had been treated for diabetes for more than 2 years (mean 8 years) and had been established on glibenclamide for over 2 years with or without adjunctive metformin therapy. Patients were studied for 6 months and randomized to continue either their present dose of glibenclamide or to be converted to an equipotent dose of gliclazide. Measurements were taken of hemostatic variables, the oxidative status of the plasma, and the redox status, both extracellularly as plasma albumin-thiols (PSH) and lipid peroxides, and intracellularly as red blood cell superoxide dismutase activity (SOD). At 3 months, diabetic control was unaltered, but there were significant improvements in the oxidative status of the gliclazide-treated patients. Lipid peroxides decreased (8.3 +/- 1.1 to 7.0 +/- .06 micromol/L, P < .01) and red blood cell SOD increased (135 +/- 21 to 152 +/- 36 microg/mL, P < .05). PSH levels were unaltered at 458 +/- 38 micromol/L, whereas they had decreased significantly in the glibenclamide patients (414 +/- 34 micromol/L, P < .05), resulting in a significant difference between the 2 treatment groups (P < .004). Platelet reactivity to collagen also improved in the gliclazide-treated patients, decreasing from 65.1% +/- 14% to 50.8% +/- 24% (P < .01). The reactivity of the platelets remained unaltered in the glibenclamide patients. At 6 months, the significant differences between the 2 treatment groups remained. Hence, gliclazide was shown in a clinical study to have free radical scavenging activity independent of glycemic control.

Adult↗

PubMed2000

Characterization of (125)I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors.

The properties of an (125)I-labeled structural analog of 2, 3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3. 1]nonan-3beta-yl]benzamide (MABN), (125)I-IABN, are described. (125)I-IABN was developed as a high-affinity radioligand selective for the D2-like (D2, D3, and D4) dopamine receptor subtypes. (125)I-IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sf9 and HEK 293 cells. (125)I-IABN binds with 7- to 25-fold lower affinity to human D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation constants (Kd) calculated from kinetic experiments were in agreement with equilibrium Kd values obtained from saturation binding studies. Saturation plots of the binding of (125)I-IABN with rat caudate membrane preparations were monophasic and exhibited low nonspecific binding. The pharmacologic profile of the binding of (125)I-IABN to rat caudate was consistent with a D2-like receptor, suggesting that the ligand binds primarily to D2 dopamine receptors. In addition, IABN was found to bind with low affinity to D1 dopamine receptors, as well as to the sigma1 and sigma2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that (125)I-IABN selectively labels the striatum and the olfactory tubercle area, which is consistent with the labeling of D2-like receptors. IABN blocks dopamine-dependent inhibition of adenylyl cyclase activity at D2 or D4.4 receptors expressed in HEK cells. Therefore, (125)I-IABN appears to be a high-affinity, selective antagonist at D2-like dopamine receptors. Finally, a unique property of the azabicyclononane benzamide (125)I-IABN compared to previously studied substituted benzamides is that the binding of this radioligand is not effected by variations in Na(+) concentration.

Animals↗

PubMed2005

The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.

4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pK(B) = 8.6 +/- 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidin-4-yl}methanone O-ethyloxime (Sch-C; SCH 351125), 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R)-2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinyl]carbonyl}pyrimidine (Sch-D; SCH 417,690), 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenyl-propyl)cyclohexanecarboxamide (UK-427,857), and N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK779) blocked the binding of both chemokines (125)I-MIP-1alpha (also known as (125)I-CCL3, (125)I-LD78) and (125)I-RANTES ((125)I-CCL5), 873140 was an ineffectual antagonist of (125)I-RANTES (regulated on activation normal T cell expressed and secreted) binding (but did block binding of (125)I-MIP-1alpha). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 (RANTES) (as did the other antagonists), indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe-dependent, consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of <0.004 h(-) (1) (t(1/2) > 136 h). Coadministration studies of 873140 with the four other allosteric antagonists yielded data that are consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. Although these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor, as indicated by their differential effects on the binding of (125)I-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.

Animals↗