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S Arbilla

Publications and source records attributed to S Arbilla.

At least 19 recordsLinked to original sources
PubMed1998

Functional uroselectivity.

Alpha1-adrenoceptors mediating sympathetic tone to smooth muscle cells are located within the prostatic tissue, bladder base and in the proximal urethra, but are also widely distributed within a large number of tissues, especially the vascular beds and the central nervous system. Compounds clinically used in the symptomatic treatment of benign prostatic hyperplasia must therefore exhibit functional uroselectivity. This means that they should preferentially act on the lower urinary tract rather than the vasculature or central nervous system. Few clinically used alpha1-adrenoceptor antagonists show selectivity for the alpha1a/A-adrenoceptor subtype, whereas most of them have similar affinities for the three cloned subtypes (alpha1a-, alpha1b- and alpha1d-adrenoceptors). Recent data from in vitro studies assessing pharmacological uroselectivity and from in vivo models evaluating functional uroselectivity challenged the relevance of the affinity or the selectivity for a known alpha1-adrenoceptor subtype in predicting functional uroselectivity. They suggest instead that another subtype, like the alpha1L-adrenoceptor, might be functionally involved. In conclusion, the actual state of knowledge on alpha1-adrenoceptor subtype distribution and function, does not support a role of pharmacological uroselectivity in predicting functional uroselectivity. Furthermore, functional uroselectivity can be achieved in the absence of selectivity for the alpha1-adrenoceptor subtypes described so far.

Adrenergic alpha-Antagonists↗
PubMed1998

Anti-inflammatory properties of mizolastine after oral administration on arachidonic acid-induced cutaneous reaction in the rat.

The anti-inflammatory effect of mizolastine (CAS 108612-45-9, SL85.0324-00), a new non-sedative histamine H1-receptor antagonist, was assessed in comparison to loratadine, terfenadine and pyrilamine. Intraplantar injection of arachidonic acid (AA) into the rat paw was followed by a rapid and sustained (> or = 4h) inflammatory oedema. Mizolastine (0.1 to 10 mg/ kg p.o.) inhibited in a dose-dependent manner the time course of the AA-induced paw inflammation as from the dose of 0.1 mg/kg p.o. This effect was maintained for at least the 4 h of observation (-44% at 0.3 mg/kg p.o.) suggesting a long lasting action of mizolastine. Although with higher maximal effect, a similar time course of response was observed with dexamethasone at 0.1 mg/kg p.o. In contrast, at anti-histamine, doses, the histamine H1-receptor antagonists terfenadine (1 to 30 mg/kg p.o.), loratadine (10 mg/kg p.o.), and pyrilamine (10 mg/kg p.o.) failed to inhibit significantly the inflammatory action of AA. Moreover, under conditions of H1-receptors blockade (e.g. when co-administered with pyrilamine or loratadine (10 mg/kg p.o.), the inhibition by mizolastine (0.3 mg/kg) of AA-induced inflammation was unchanged. This suggests that the anti-inflammatory effect of mizolastine was unrelated to its histamine H1-receptor antagonist properties. It is proposed that a primary effect on the lipoxygenase pathway may contribute to this action of mizolastine. This is based on the observations that mizolastine inhibits 5-lipoxygenase activity in vitro. Furthermore, a high dose of mizolastine (50 mg/kg) did not affect the inflammatory response to carrageenin which is mediated by the cyclooxygenase pathway. Together, these data indicate that mizolastine is orally effective in this animal model for cutaneous inflammation. Combined with its blockade of histamine H1-receptors, this property may contribute to its possible use in allergic inflammation or other inflammatory states.

Administration, Oral↗
PubMed1998

Effect of mizolastine on visceral sensory afferent sensitivity and inflammation during experimental colitis.

In the present study the effect of mizolastine (CAS 108612-45-9, SL85.0324-00) a novel potent histamine H1-receptor antagonist, on 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis, a rat model of inflammatory bowel disease, was investigated to determine whether mizolastine has anti-inflammatory properties. Treatment with TNBS resulted in increased nociception in response to rectal balloon distension and caused intestinal damage, tissue oedema and inflammation. Oral mizolastine (0.03-3.00 mg/kg given 1 h before and once daily for 3 days after TNBS treatment) significantly (p < 0.05) reduced nociception (49% at 0.3 mg/kg), gross intestinal damage (78% at 3.0 mg/kg), histological damage (54% at 3.0 mg/kg), intestinal tissue weight (69% at 3.0 mg/kg) and myeloperoxidase activity (66% at 3.0 mg/kg). In contrast, the H1-receptor antagonist terfenadine tested under the same experimental conditions at 3-30 mg/kg was without significant effect. It is concluded that, in addition to its antiallergic properties, mizolastine possesses anti-inflammatory actions that may not be related to its H1-receptor blocking properties, reducing sensory afferent hypersensitivity, damage and neutrophil infiltration observed during colitis.

Animals↗
PubMed1995

[3H]cirazoline as a tool for the characterization of imidazoline sites.

Recent studies have shown that cirazoline, an alpha 1-adrenoceptor agonist, has greater affinity than do other imidazoline or guanidinium compounds at imidazoline recognition sites. In this report we used [3H]cirazoline as a probe to characterize imidazoline recognition sites present in membrane homogenates of rat brain and kidney as well as pancreatic beta HIT T15 cells. Specific binding of [3H]cirazoline to these various homogenates was saturable and reversible and was resolved into two classes of high affinity binding sites. Competition inhibition studies of [3H]cirazoline binding to these different membrane preparations were performed with alkaloid, phenylethylamine, imidazoline, and guanidinium compounds. Catecholamines and non-imidazoline adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or yohimbine did not compete with [3H]cirazoline (Ki > 10 microM). Under our experimental conditions, only guanidinium and imidazoline derivatives had high affinities for [3H]cirazoline binding sites. Unlabeled cirazoline, clonidine, bromoxidine, idazoxan, and amiloride had the highest affinities with this respective rank order. These results suggest that [3H]cirazoline is a novel high affinity radioligand that specifically labels nonadrenergic imidazoline-guanidinium sites in the brain, kidney, and beta cells. Furthermore, the obtained rank order of inhibition suggests that [3H]cirazoline binding does not distinguish between I1 and I2 sites. In addition, we compared the specific binding of [3H]cirazoline with that of the alpha 2-adrenoceptor antagonist [3H]rauwolscine in chinese hamster ovary (CHO) cell lines stably expressing human alpha 2C2-, alpha 2C4-, and alpha 2C10-adrenoceptor subtypes. Using [3H]rauwolscine as a probe, each of these transfected cell lines expressed high levels for the three different alpha 2-adrenoceptor subtypes (Bmax values were between 2 and 7 pmol.mg-1 protein). In contrast, none of these cell lines displayed measurable imidazoline recognition sites. In summary, [3H]cirazoline is a novel high affinity radioligand that specifically labels imidazoline recognition sites without significant alpha- or beta-adrenoceptor binding. Furthermore, our results using alpha 2-adrenoceptor transfected cells confirm that the imidazoline recognition sites and each of the cloned alpha 2-adrenoceptor subtypes represent distinct macromolecular entities.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1995

Binding of [3H]cirazoline to an imidazoline site in rat brain and kidney membranes.

Two classes of high-affinity sites for [3H]cirazoline were characterized in rat brain and kidney membranes. In both tissues, the binding parameters for the high- and low-affinity sites are similar with Bmax values of approximately 50 fmol/mg protein, Kd approximately 0.6 nM and Bmax approximately 470 fmol/mg protein, Kd approximately 11 nM respectively. Inhibition studies of [3H]cirazoline binding to the lower affinity site revealed that only guanidinium or imidazoline derivatives compete with the specific binding of this radioligand. Our results suggest that [3H]cirazoline could be used as a novel ligand to label the non-adrenergic imidazoline-preferring sites.

Animals↗
PubMed1994

Expression of alpha 1-adrenoceptor subtypes in rat tissues: implications for alpha 1-adrenoceptor classification.

We report here the mapping of the mRNA distribution of three different alpha 1-adrenoceptor subtypes (alpha 1b, alpha 1c and alpha 1d) in various rat tissues. cDNA fragments covering the region from the fifth to seventh putative transmembrane spanning domains of these three alpha 1-adrenoceptor subtypes were generated from rat hippocampus using reverse transcription coupled to polymerase chain reaction (PCR). These three alpha 1-adrenoceptor cloned cDNA fragments were then used as subtype-selective cDNA probes in Northern blot analysis. Of the three specific DNA probes only the rat alpha 1b-adrenoceptor probe hybridized to mRNA of rat liver. The rat alpha 1c-adrenoceptor probe hybridized to a mRNA species of 3.7 kb in tissues that have been reported to contain the classical pharmacologically-defined alpha 1A-adrenoceptor such as hippocampus, vas deferens, lung and salivary gland. Also, a major mRNA transcript of 2.7 kb was detected in hippocampus, vas deferens and lung, using the rat alpha 1d-adrenoceptor probe. In addition, pharmacological characterization of [3H]prazosin binding to three stably transfected mammalian cell-lines expressing one of the three alpha 1-adrenoceptor subtypes cloned to date (namely, alpha 1b--of the hamster smooth muscle DDT1-MF2 cell-line, the bovine brain alpha 1c--and the rat cerebral cortical alpha 1d-adrenoceptors) was performed. Of the three cloned alpha 1-adrenoceptor subtypes that alpha 1c-adrenoceptor showed a similar pharmacological profile to that of the classical alpha 1A-adrenoceptor of rat salivary gland. Our data on the pharmacological profile and expression pattern of the alpha 1c-adrenoceptor indicate, in contrast to earlier claims (Schwinn et al., J. Biol. Chem. 265, 1990), that this subtype is in fact the classical pharmacologically-defined alpha 1A-adrenoceptor subtype.

Amino Acid Sequence↗
PubMed1993

Expression and properties of recombinant alpha 1 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 forms of the rat GABAA receptor.

The interaction of omega (benzodiazepine) modulatory drugs with transiently expressed alpha 1 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 forms of the rat GABAA receptor was investigated using [3H]flumazenil as a probe in in vitro radioligand binding assays. The imidazopyridines alpidem and zolpidem exhibited pronounced selectivity for the alpha 1- compared to the alpha 5-containing construct, whereas omega (benzodiazepine) site modulatory compounds from other chemical series including diazepam, tetrazepam, zopiclone, triazolam, bretazenil and midazolam behaved as relatively non-selective drugs. In the presence of 10 microM gamma-aminobutyric acid (GABA) the potencies of diazepam, flunitrazepam and midazolam to inhibit [3H]flumazenil binding to the alpha 1-construct were increased 3 to 5 fold, whereas with 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate methyl ester a 2.5-fold reduction in potency was observed. Similar modulatory effects of GABA were obtained with these drugs, using the alpha 5-construct. We suggest that these GABA shift determinations of [3H]flumazenil binding can be used as a rapid test to evaluate the intrinsic activities of omega modulatory compounds.

Animals↗
PubMed1992

SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist: in vitro pharmacological profile.

One novel, potent and selective alpha-2 adrenoceptor antagonist is 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2- propylpyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418). It inhibits with high affinity the radioligand binding to rat cortical alpha-2 adrenoceptors, as well as to human platelet alpha-2 adrenoceptors labeled with [3H]idazoxan (Ki = 7 nM). SL 84.0418 has low affinity for alpha-1 adrenoceptors labeled with [3H]prazosin (Ki = 3.3 microM). In vitro, SL 84.0418 has no alpha agonist properties, whereas it is a potent alpha-2 adrenoceptor antagonist at both pre- and postsynaptic alpha-2 adrenoceptors. In contrast, it possesses low potency as an antagonist at postsynaptic alpha-1 adrenoceptors demonstrating a more than 1000-fold selectivity toward alpha-2 compared with alpha-1 adrenoceptors. In the same tests, the alpha-2 adrenoceptor antagonist idazoxan had a selectivity ratio of 200. SL 84.0418 is the racemic mixture of two enantiomers, SL 86.0715 [(+) enantiomer] and SL 86.0714 [(-) enantiomer]. The alpha-2 adrenoceptor blocking activities reside with SL 86.0715. Similar to idazoxan, SL 84.0418 increases in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine from rat hypothalamic slices through the blockade of the presynaptic inhibitory alpha-2 adrenoceptors. In isolated hamster adipocytes, SL 84.0418 potently antagonizes the inhibition of lipolysis induced by UK 14,304. In addition, SL 84.0418 inhibits epinephrine-induced aggregation of rabbit platelets, effects mediated by postsynaptic alpha-2 adrenoceptors. SL 84.0418 does not inhibit (IC50 > 1,000 nM) radioligand binding to other receptors or recognition sites, nor does it inhibit calcium, sodium or potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1992

Comparative in vivo and in vitro regional selectivity of central omega (benzodiazepine) site ligands in inhibiting [3H]flumazenil binding in the rat central nervous system.

The in vivo selectivity for central omega (benzodiazepine) modulatory site subtypes of ligands from several chemical classes has been evaluated by measuring the displacement of the in vivo binding of [3H]flumazenil to several rat central nervous system structures differentially enriched in omega 1 and omega 2 sites. This labeling was prevented in a dose-related manner by the i.p. administration, 30 min before the radioligand, of several benzodiazepine derivatives, the cyclopyrrolone derivatives suriclone and zopiclone, the triazolopyridazine derivative CL 218,872 and the imidazopyridine derivative zolpidem. Most of the benzodiazepine derivatives studied displayed in vivo some selectivity for omega 2-enriched structures. In contrast, oxoquazepam and CL 218,872 were 2- to 3-fold more potent at preventing [3H]flumazenil binding in omega 1-enriched (cerebellum) than in omega 2-enriched structures. Maximal inhibitions by zolpidem of in vivo [3H]flumazenil binding [cerebellum (100%) > cerebral cortex (79%) > or = striatum (74%) > hippocampus (52%) > spinal cord (37%)] were related to the relative omega 1/omega 2 distribution ratio in each structure. These differences did not result from an uneven distribution of this compound in the central nervous system. Quantitative autoradiographic studies performed on 30 central nervous system regions showed a strong correlation between the in vitro and in vivo regional selectivity of zolpidem. For all the drugs studied there was a significant global correlation between their potency at inhibiting [3H]flumazenil binding in vitro and in vivo either in the cerebellum (P < .001) or in the spinal cord (P < .01) and between the in vitro and in vivo cerebellum/spinal cord selectivity. The differential in vivo selectivity of zolpidem may account for the reported hypnoselective profile of this imidazopyridine in the rodent.

Animals↗
PubMed1990

Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites.

Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors.

Animals↗
PubMed1990

Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs.

The names omega 1-, omega 2-, and omega 3-receptor subtypes have recently been proposed to replace the nomenclature of BZ1, BZ2 and BZp receptors in order to avoid a nomenclature exclusively linked to the benzodiazepine (BZ) structure or to a regional localization. The multiplicity of pharmacological actions of currently available anxiolytics may be due to their lack of selectivity for omega-receptor subtypes. The idea that a receptor-subtype selective drug will offer a more specific therapeutic profile is widely accepted. In the field of preferential anxiolytic or hypnotic drugs, imidazopyridines represent a new chemical and therapeutic class possessing selectivity for omega-receptor subtypes. Of these, alpidem (6-chloro-2-(4-chloro-phenyl)-N,N-dipropylimid-azo[1,2-a] pyridine-3-acetamide) behaves preferentially as an anxiolytic drug in both animal models and man. Receptor-binding studies using alpidem either as a displacer or as a radioligand indicate that the compound has a high affinity for omega 1- and for omega 3- but not for omega 2-receptors. In the human brain, the binding of [3H]-alpidem to omega 1- and omega 3-receptors occurs with a Kd of 1.67 nM and 0.33 nM respectively. The binding of [3H]-alpidem to omega 1-receptors in the rat cerebral cortex with a Kd of 1.5 nM is enhanced by GABA, and in contrast to anxiolytics of the benzodiazepine type, is unaffected by chloride ions and pentobarbital. In conclusion, the affinity of alpidem for the omega 1-receptor is allosterically influenced by the activation of the GABAA receptor but not by other components of the same receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Imidazopyridines as a tool for the characterization of benzodiazepine receptors: a proposal for a pharmacological classification as omega receptor subtypes.

At present, the nomenclature of benzodiazepine (BZ) receptors is based on its historical association with the BZ structure. However, it is mainly through the new compounds chemically unrelated to BZs that the central and peripheral subtypes of BZ receptors have been characterized. We therefore propose the nomenclature of a greek letter omega, as omega 1, omega 2 and omega 3 to designate respectively the central BZ1, BZ2 and the peripheral BZ receptor. Among the several classes of non-BZ drugs with affinity for different receptors, the imidazopyridines provide a valuable tool for the characterization of omega receptor subtypes. Most BZs are non selective ligands for the central omega 1 and omega 2 receptors while the selectivity for omega 1 receptor subtypes is present in several non BZ chemical series: imidazopyridines (zolpidem), triazolopyridazines (CL 218872), betacarbolines (beta-CCE) and pyrazoloquinolines (CGS 8216). Selective ligands for the omega 2 subtype are not available so far. The so called peripheral BZ receptor is also present in the central nervous system, therefore the proposed nomenclature of omega 3 receptors resolves this paradox because it does not designate location and it is defined in terms of pharmacological specificity. Selective ligands for omega 3 receptors include the BZ Ro 5-4864, and the isoquinolinecarboxamide PK 11195, while the imidazopyridine alpidem is the ligand with the highest affinity for this receptor subtype.

Animals↗
PubMed1988

Modulation of the electrically evoked release of 5-[3H]hydroxytryptamine from rat cerebral cortex: effects of alpidem, CL 218872, and diazepam.

The effect of omega (benzodiazepine)-receptor agonists, antagonists, and inverse agonists on the electrically evoked release of 5-[3H]hydroxytryptamine ([3H]5-HT) was studied in superfused slices of the rat frontal cerebral cortex. The electrically evoked release of [3H]5-HT was enhanced by nanomolar concentrations of diazepam and the selective omega 1-receptor agonists alpidem and CL 218872. The omega 1/omega 2- and omega 1-receptor antagonists flumazenil and CGS 8216, respectively, did not modify the electrically evoked release of [3H]5-HT. The omega 3-receptor agonist Ro 5-4864 and the omega 1-receptor inverse agonist ethyl-beta-carboline-3-carboxylate on their own did not affect the electrically evoked release of [3H]5-HT. On the other hand, the inverse agonist 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester (DMCM), at micromolar concentrations, inhibited both the spontaneous and the evoked release of [3H]5-HT. The facilitation of the electrically evoked release of [3H]5-HT by diazepam, alpidem, or CL 218872 was potentiated by gamma-aminobutyric acid (GABA). Exposure to flumazenil and CGS 8216 antagonized the facilitation by diazepam, alpidem, or CL 218872 of [3H]5-HT release. The inhibition of the release of [3H]5-HT by DMCM was not modified by exposure to either flumazenil, CGS 8216, or GABA. The inhibitory effect of DMCM was not observed when monoamine oxidase activity was inhibited by pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗