Ganglioside GM1 and its semisynthetic lysogangliosides reduce glutamate neurotoxicity by a novel mechanism.
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Animals↗
Biomedical subjects
E Costa
Publications and source records attributed to E Costa.
Molecular parameters of semisynthetic derivatives of gangliosides and sphingosine in monolayers at the air-water interface.
The molecular parameters (molecular area, surface potential, collapse pressure, dipole moment contributions) of semisynthetic derivatives of ganglioside GM1 and of sphingosine were studied in lipid monolayers at the air-NaCl (145 mM, pH 5.6) interface at 22 +/- 0.3 degrees C. The chemical modifications included alterations of the fatty acyl chain moiety linked to the 2-amino position of the sphingosine (Sph) base. The compounds studied were PKS-1 (N-acetyl Sph), PKS-2 (N-chloroacetyl Sph), PKS-3 (N-dichloroacetyl Sph), PKS-4 (N-trichloroacetyl Sph), Lyso-GM1 (ganglioside GM1 lacking the N-linked fatty acyl chain and the N-acetyl group on the sialic acid), Liga-4 (N-acetyl, lyso[NeuAc]GM1) and Liga-20 (N-dichloroacetyl, lyso[NeuAc]GM1). Relatively small modifications of the chemical structure of sphingolipids introduce dramatic consequences on their surface molecular properties. The absence of the long chain fatty acyl moiety and of the N-acetyl group on the neuraminic acid in Lyso-GM1 leads to a more condensed behavior and to an increase of the collapse pressure compared with GM1. The acetylation or chloroacetylation at the 2-amino position in Liga-4 and Liga-20 induce an expansion of the surface pressure-area isotherm and a decrease of the collapse pressure. The limiting molecular areas of GM1 derivatives, taken at the collapse pressure point, are consistent with the oligosaccharide chain being oriented approximately perpendicularly to the interface. Sphingosine shows a liquid expanded isotherm. The acetylation and successive chlorination of the acetyl residue at the 2-amino position of Sph cause a progressive increase in the limiting molecular area. The variation of the resultant dipole moment under compression, calculated from the surface potential values, suggests the reorientation of selective groups within these molecules that depend on the degree of intermolecular packing. Thermodynamic-geometric correlations on the basis of the molecular parameters of these derivatives suggest that small alterations of the substituent group at the 2-amino position of Sph could have large and amplified consequences on the type, curvature and stability of the possible self-aggregated structure that these lipids may form in aqueous medium.
Air↗
ACTH-induced mitochondrial DBI receptor (MDR) and diazepam binding inhibitor (DBI) expression in adrenals of hypophysectomized rats is not cause-effect related to its immediate steroidogenic action.
Diazepam binding inhibitor (DBI) is a 10-kDa polypeptide that is enriched in steroidogenic cells such as adrenocortical, Leydig, and glial cells. In these cells, DBI and some of its processing products bind to the mitochondrial DBI receptor (MDR), located on the outer mitochondrial membrane, and stimulate pregnenolone formation by facilitating cholesterol access to the inner mitochondrial membrane where the cytochrome P-450 side chain cleavage enzyme is located. To determine whether the ACTH-induced increase in adrenal steroidogenesis occurs via changes in DBI and MDR expression the adrenal content of DBI-like immunoreactivity (DBI-LI), the MDR density, and the expression of mRNAs encoding for DBI and MDR were studied in hypophysectomized rats treated with vehicle or ACTH. After 9 days from the hypophysectomy, the levels of DBI-like immunoreactivity (DBI-LI) and DBI-mRNA declined to approximately 20% of their normal value; in contrast MDR-density and MDR-mRNA levels were reduced by 50-60% and were associated to a similar decrease in the activity of type A monoamine oxidase, a marker for mitochondrial proteins. Prolonged administration of ACTH-R (ACTH in saline containing 16% gelatin, 15 U/kg/day, from day 7 after surgery) to hypophysectomized rats, completely restored DBI and MDR adrenal expression to values similar to those of sham-operated rats. Our results indicate that ACTH, probably acting at the transcriptional level, is required for the normal expression of DBI and MDR in adrenal cortex. Changes in DBI and MDR expression after ACTH administration were not temporally related to the immediate steroidogenesis induced by ACTH, and may reflect its long-term trophic action on adrenocortical cells.
Adrenal Glands↗
Adrenal steroids mediate the increase of hippocampal nerve growth factor biosynthesis following bicuculline convulsions.
Northern blot analysis of nerve growth factor (NGF) messenger ribonucleic acid (mRNA), together with a two-site enzyme immunoassay for NGF protein, showed that a convulsive dose of bicuculline (0.4 mg/kg, IV) induced a rapid (within 1 hour) three-fold increase in hippocampal NGF mRNA. This increase was followed by a significant increase in NGF protein 5 hours later. No changes were detected in the cerebral cortex. The increase of rat hippocampal NGF mRNA and protein content was associated with an increase in plasma corticosterone content. Both responses were completely prevented by a pretreatment with diazepam (5 mg/kg, IP), which suggested that adrenal steroids might be a stimulus underlying the rapid increase in NGF biosynthesis following bicuculline convulsions. Therefore, we tested to determine whether a convulsive dose of bicuculline could increase NGF mRNA in adrenalectomized and sham-operated rats. Bicuculline increases hippocampal NGF mRNA in sham-operated rats, but not in adrenalectomized rats despite the presence of convulsions in both experimental groups. Moreover, in adrenalectomized rats, dexamethasone (0.5 mg/kg, SC) could partly restore the increase in hippocampal NGF mRNA content induced by bicuculline convulsions; thus, adrenal steroids might have an essential role in the induction of hippocampal NGF biosynthesis elicited by bicuculline convulsions.
Adrenal Cortex Hormones↗
Nuclear signal transduction via immediate early genes in neurons and glia.
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Animals↗
Alpha-1-antitrypsin deficiency and viral infections.
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Humans↗
Regional and interspecies differences in brain progesterone metabolism.
Metabolites of [3H]progesterone were studied in slices prepared from different brain regions of male rat, mouse, and monkey. The major metabolites were 5 alpha-dihydroprogesterone (5 alpha-DHP) and 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP) in rat brain slices, 5 alpha-DHP and 20 alpha-dihydroprogesterone (20 alpha-DHP) in mouse brain slices, and 20 alpha-DHP in monkey brain slices. In rat olfactory bulb slices, 5 alpha-DHP represented 25.2 +/- 3.3% of total radioactivity and 3 alpha,5 alpha-THP 17.5 +/- 2.8%, whereas in rat medulla oblongata slices, 5 alpha-DHP was 31.3 +/- 3.5% and 3 alpha,5 alpha-THP 5.4 +/- 1.5% of total radioactivity. In slices from other rat brain regions, both metabolites represented 12-20% of total radioactivity. The highest metabolite content in mouse brain was also detected in olfactory bulb slices, where 5 alpha-DHP represented 16.6 +/- 4.6% and 20 alpha-DHP 9.5 +/- 2.3% of total radioactivity. In cortical and corpus callosum slices of monkey brain, 26.8 +/- 4.4% and 2.4 +/- 0.5% of total radioactivity, respectively, were converted to 20 alpha-DHP, and less than 3% of total radioactivity could be attributed to any of the other metabolites detected. The 3 alpha, 5 alpha-THP content in both rat and monkey brain was below 1 nM, but increased in rat brain to 6.7 +/- 2.5 nM after electroshock. Endogenous 3 alpha,5 alpha-THP might play an important role in the regulation of rat behavior through the modulation of GABA action on the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo.
Evidence that neurosteroids are potent modulators of the action of GABA at GABAA receptors has prompted the investigation of the mechanism that controls brain neurosteroid synthesis by glial cell mitochondria in vivo. In vitro studies suggest that the interaction of the diazepam binding inhibitor (DBI)--a polypeptide that is abundant in steroidogenic cells--with glial mitochondrial DBI receptors (MDRs) is a crucial step in the physiological regulation of neurosteroid biosynthesis. MDRs bind 4'-chlorodiazepam (4'-CD), N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN-1-27), and the isoquinoline carboxamide PK 11195 with high affinity, and these ligands have been used to investigate whether the stimulation of glial MDRs increases brain pregnenolone production in vivo. Adrenalectomized and castrated (A-C) male rats (to eliminate peripheral sources of pregnenolone) were pretreated with trilostane (to prevent pregnenolone metabolism to progesterone), and the pregnenolone content in brain regions dissected after fixation with a 0.8-s exposure to microwave irradiation focused to the head was determined by HPLC followed by specific radioimmunoassay. The forebrain and cerebellum of A-C rats contained 4-7 ng of pregnenolone/g of tissue, and the olfactory bulb contained 10-14 ng/g. These concentrations of brain pregnenolone are only 30-40% lower than those of sham-operated rats. In contrast, the plasma pregnenolone content of sham-operated rats was 2-3 ng/ml, but it was only 0.15-0.20 ng/ml in the plasma of A-C rats. In A-C rats, treatment with the MDR ligands 4'-CD and FGIN-1-27 increased the pregnenolone content in the brain but failed to change the plasma or peripheral tissue content of this steroid. The effect of 4'-CD on brain pregnenolone content was maximal (70-100% increase) at the dose of 18 mumol/kg, 5-10 min after intravenous injection. The effect of oral administration of FGIN-1-27 on brain pregnenolone content was maximal (80-150% increase) at doses of 400-800 mumol/kg and peaked at approximately 1 h. That this effect of FGIN-1-27 was mediated by the MDR was documented by pretreatment with the MDR partial agonist PK 11195 (100 mumol/kg, i.p.). PK 11195 did not affect basal brain pregnenolone content but prevented the accumulation of brain pregnenolone induced by FGIN-1-27. FGIN-1-27 and 4'-CD failed to increase the brain concentration of dehydroepiandrosterone in A-C rats. These data suggest that glial cell MDRs play a role in neurosteroid biosynthesis in vivo.
Adrenalectomy↗
During anesthetic-induced activation of hypothalamic pituitary adrenal axis, blood-borne steroids fail to contribute to the anesthetic effect.
Anesthetic doses of ethanol (100 mmol/kg p.o.), chloral hydrate (2 mmol/kg i.p.), and urethane (9 mmol/kg i.p.) induce sharp and sustained (6- to 10-fold) dose-dependent increase in rat brain pregnenolone and progesterone content. In contrast, other general anesthetics such as ketamine (0.7 mmol/kg i.p.) and pentobarbital (0.2 mmol/kg i.p.), and the sedative/hypnotic clonazepam (17 mumol/kg i.p.) decrease brain pregnenolone and progesterone content. The increase in brain pregnenolone and progesterone content fails to occur if ethanol, chloral hydrate, and urethane are administered to hypophysectomized-adrenalectomized rats suggesting that the increase of brain steroids requires the hypophysis and probably originates in peripheral tissues and not in brain. The administration to hypophysectomized rats of 5 IU/kg of ACTH produces a brain pregnenolone and progesterone accumulation by an extent comparable to that elicited by anesthetic doses of ethanol, chloral hydrate, or urethane in intact animals. However, the increase in brain pregnenolone and progesterone content induced by ACTH is devoid of anesthetic or sedative effects and does not appear to change central GABAergic tone. In fact, ACTH, unlike allopregnanolone and allodeoxicorticosterone, failed to delay the onset of isoniazid-induced seizures, to reduce the fear of novelty in the elevated plus maze test as inferred by the increase in the number of entries or the time spent in the open arm. Thus, the data suggest that blood-borne steroids cannot function as precursors of brain neurosteroid modulators acting on GABAA receptor.
Adrenal Glands↗
Glutamate-activated currents in outside-out patches from spiny versus aspiny hilar neurons of rat hippocampal slices.
The desensitization rate of non-NMDA glutamate receptors was investigated in outside-out membrane patches obtained from morphologically identified spiny "mossy cells" (SMCs) and aspiny hilar interneurons (AHIs) in young rat hippocampal slices. The fast application of a 1 mM step of L-glutamate for 50-100 msec in the presence of TTX and dizolcipine (MK-801) onto patches excised from these neurons produced large glutamate-activated currents (GACs) that decayed with a single or double exponential time course despite the continued presence of agonist. These desensitization rates of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-sensitive receptors differed markedly between patches obtained from the two cell types. The fast time constant of desensitization in AHIs (n = 34) averaged 3.3 +/- 0.93 msec (mean +/- SD), while that of SMCs (n = 57) averaged 6.8 +/- 2.0 msec. Current-voltage relationships of the GACs did not differ between SMCs and AHIs, with comparable reversal potentials and no evidence of inward rectification. We also failed to observe significant Ca2+ permeability in either cell type. However, brief (< 1 msec) pulses of 1 mM glutamate produced rapidly decaying GACs with distinct kinetics in the two neuronal classes. Furthermore, analysis of the single glutamate-activated channel currents in outside-out patches from hilar neurons revealed a larger predominant single-channel current in AHIs versus SMCs. Lastly, we observed a greater sensitivity to cyclothiazide in SMCs versus AHIs, with half-maximal removal of desensitization being 90 mM and 200 mM, respectively. Taken together, these differences in GACs between SMCs and AHIs might indicate a functional correlate to the substantial heterogeneity in the molecular structure of glutamate receptor subunits or might be related to posttranslational modifications of these subunits, perhaps provided by the unique microenvironment in the spines covering SMCs.
Action Potentials↗
Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus.
Among the non-NMDA (non-N-methyl-D-aspartic acid) glutamate receptors, the AMPA (alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid) selective receptors are characterized by a fast occurring desensitization. We and others have searched for specific modifiers of the rapid desensitization of AMPA responses in hippocampal slices using the patch-clamp technique. Aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone) and diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) (1 mM) increased glutamate-activated currents recorded from voltage-clamped CA1 pyramidal neurons in presence of 5 microM MK-801 (dizocilpine; 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine) by 2.5 fold. Cyclothiazide (3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzoth ia diazine-7-sulfonamide 1,1-dioxide) (100 microM), a chemical congener of diazoxide, completely removed the desensitization of the AMPA response measured with fast application in excised outside-out patches. At this concentration cyclothiazide produced an 18 fold enhancement of the glutamate current. Eighteen diazoxide analogues (2H-1,2,4-benzothiadizines: IDRA 2-19) were then tested but none of them was as effective as diazoxide. Three analogues of cyclothiazide (3,4-dihydro-2H-1,2,4-benzothiadiazines: IDRA 20-22) were also tested and none of them were as potent as the parent compound. However, IDRA 21 produced a response 3 times larger than diazoxide. Moreover, while cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor desensitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptor desensitization preferentially. These results suggest that similarly to NMDA receptors the structure of AMPA receptors may include a center that regulates desensitization.
Action Potentials↗
Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition?
The modulation of GABA activity by 3 alpha-OH-DHP (allopregnanolone, 3 alpha-hydroxy-5 alpha-pregnan-20-one) and PS (pregnenolone sulfate) has been studied in native GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors expressed in the 293 human embryonic kidney cell line (HEK 293). In cortical neurons 3 alpha-OH-DHP positively modulates GABA elicited Cl- currents while PS at 10 microM negatively modulates (50% decrease) this GABA response, but at 10 nM PS positively modulates the GABA current (40% increase). Both neurosteroids are equally active on various types of recombinant GABAA receptors, except for alpha 6 beta 1 gamma 2 receptors which are less sensitive to the positive allosteric modulation by 3 alpha-OH-DHP. In contrast the presence of the gamma 1 subunit doubles the efficacy of 3 alpha-OH-DHP. The negative modulation of PS is similar in recombinant GABAA receptors including various molecular forms of alpha or gamma units. A direct activation of Cl- current by 3 alpha-OH-DHP was observed in native and recombinant receptors but its efficacy on the various molecular forms of GABAA receptor tested was always smaller than that of identical concentrations (10 microM) of GABA.
Allosteric Regulation↗
Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.
The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2- (4-fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the gamma-aminobutyric acidA receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict-punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)
Aggression↗
Protection by gangliosides against glutamate excitotoxicity.
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Animals↗
Gene expression of Na+/Ca2+ exchanger in brain ischemia.
It is known that intracellular Ca2+ is overloaded during ischemia as a result of the altered activity of the Na+/Ca2+ exchanger, one of the major pathways of Ca2+ efflux. But the molecular mechanism of the alteration is still unknown. We cloned a -500bp cDNA fragment of rat cerebellar Na+/Ca2+ exchanger gene. Using this cDNA fragment as the probe, we found that the Na+/Ca2+ exchanger mRNA is widely distributed in rat central and peripheral nervous system such as in cerebra, heart, lung and kidney. Using focal cerebral ischemic model, we detected the gene expression of Na+/Ca2+ exchanger in ischemic brain by Northern bolt and in situ hybridization, and found that in ischemic tissues, the mRNA level of Na+/Ca2+ exchanger is lowered.
Animals↗
Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex.
The 2-aryl-indole-3-acetamide derivatives, 2-hexyl-indole-3-acetamide (FGIN-1-27) and 2-hexyl-indole-3-acetamide-N-benzene-tricarboxylic acid (FGIN-1-44) displaced [3H]1-(2-chlorophenyl)-N-methyl-N-(1- methylpropyl)-3-isoquinoline-carboxamide([3H]PK 11195) and [3H]4-chlorodiazepam ([3H]4'CD) from binding sites located on the rat brain mitochondrial DBI receptor complex (MDRC) with Ki values in the nanomolar range. Both 2-aryl-indole-3-acetamide derivatives acted as agonists at the MDRC and thereby stimulated the rate of pregnenolone synthesis in isolated rat brain mitochondria; this effect was inhibited by PK 11195, an MDRC ligand that does not possess steroidogenic activity. FGIN-1-27 and FGIN-1-44 failed to bind to other transmitter receptors, including gamma-aminobutyric-A receptors. When administered orally to rats, both FGIN-1-27 and FGIN-1-44 reduced fear of novelty in the elevated plus maze test. This action was prevented by PK 11195, but not by flumazenil. FGIN-1-44, which was rapidly converted to FGIN-1-27 in the rat brain, was 3 to 4 times more potent than FGIN-1-27 in reducing fear of novelty because of its greater bioavailability. FGIN-1-27 increased the brain pregnenolone content in adrenalectomized-castrated rats pretreated with trilostane (in order to prevent metabolism of pregnenolone to progesterone). This increase was blocked by pretreatment with PK 11195. Although FGIN-1-27 and FGIN-1-44 increased the corticosterone concentration in adrenal glands and plasma of hypophysectomized rats in a PK 11195-sensitive manner, both drugs failed to increase adrenal steroidogenesis in sham-operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Glands↗
Topology of two DBI receptors in human lymphocytes.
High-affinity binding sites for the isoquinoline carboxamide PK 11195 and 4'-chlorodiazepam (4'CD) in human lymphocytes are recognized by two putative endogenous ligands: diazepam binding inhibitor (DBI) and protoporphyrin IX. We have now demonstrated that several synthetic DBI peptides--analogues to naturally processed human DBI (H-DBI) fragments--differ from protoporphyrin IX in the manner in which they displace [3H]PK 11195 and [3H]4'CD from binding sites associated with intact and cell-free lymphocyte preparations. In particular, the peptide fragments DBI37-80 and DBI37-70 displaced [3H]PK 11195 and [3H]4'CD with higher affinity from their binding sites on intact lymphocytes (Ki approximately 3-5 microM) than from the sites in the cell-free preparation (Ki approximately 20 microM). In contrast, protoporphyrin IX displaced [3H]PK 11195 and [3H]4'CD with higher affinity in the cell-free preparation (Ki - 0.4 microM) than in intact lymphocytes (Ki > 50 microM). Because DBI peptide fragments and protoporphyrin IX do not readily penetrate the plasma membrane of lymphocytes, our results suggest the existence of binding sites located both on the external face of the plasma membrane and intracellularly. The plasma membrane binding sites, recognized essentially only by DBI fragments, are termed here plasma membrane DBI receptors (PDRs). In contrast, the intracellular binding sites, recognized by both DBI fragments and protoporphyrin IX, are presumably located on mitochondria and are termed mitochondrial DBI receptors (MDRs). Immunohistochemical electronmicroscopic studies with antibodies to the synthetic peptide fragments 62-76 of the rat MDR support the hypothesis that PDRs are expressed on lymphocyte plasma membranes.
Amino Acid Sequence↗
Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors.
Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.
Allosteric Regulation↗