Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives. Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids. Absence of modifications of the pharmacological properties of the GABAA receptor complex during aging, as assessed in 3- and 24-month-old rat cerebral cortex. Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors. High-performance liquid chromatographic assay with diode-array detection for toxicological screening of zopiclone, zolpidem, suriclone and alpidem in human plasma. Ambien online references

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J Pharmacol Exp Ther. 1993 May;265(2):649-56.
Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.

Auta J, Romeo E, Kozikowski A, Ma D, Costa E, Guidotti A.

Fidia-Georgetown Institute for the Neurosciences, Washington, District of Columbia.

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)

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J Pharmacol Exp Ther. 1999 Dec;291(3):1317-23.
Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids.

Vanover KE, Edgar DM, Seidel WF, Hogenkamp DJ, Fick DB, Lan NC, Gee KW, Carter RB.

CoCensys, Inc., Irvine, California 92618, USA. kvanover

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Eur J Pharmacol. 1993 Jun 15;246(1):81-7.
Absence of modifications of the pharmacological properties of the GABAA receptor complex during aging, as assessed in 3- and 24-month-old rat cerebral cortex.

Ruano D, Machado A, Vitorica J.

Departamento de Bioquimica, Bromatologia, Facultad de Farmacia, Universidad de Sevilla, Spain.

We have investigated the possible modifications of the pharmacological properties of Type I and Type II benzodiazepine binding sites of the gamma-aminobutyric acidA (GABAA) receptor complex in cortical membranes from 3- and 24-month-old Wistar or Fischer rats. No major changes were found in the binding parameters of [3H]zolpidem (a Type I-specific ligand) or [3H]flunitrazepam (a non-selective benzodiazepine). Neither the Kd values nor the Bmax for either ligand were modified during aging in cortical membranes from Wistar or Fischer rats. Consequently, the proportion of Type I binding sites was also unmodified in aged cortical membranes. The absence of modifications of Type I and Type II binding sites was also confirmed by Cl 218,872 displacement of [3H]flunitrazepam binding in aged cortical membranes from Wistar rats. Furthermore, the [3H]muscimol binding and the allosteric interactions between Type I or total benzodiazepine binding sites and GABA binding sites also remained unaltered with aging in cortical membranes from Wistar rats. Moreover, the pattern and proportion of the [3H]flunitrazepam photoaffinity labeled peptides were also unmodified by aging. These results demonstrate the absence of modifications in Type I or total benzodiazepine binding sites of the GABAA receptor complex from adult and aged cortical membranes in Fischer or Wistar rats.

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Mol Pharmacol. 1993 Aug;44(2):437-42.
Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors.

Wafford KA, Bain CJ, Whiting PJ, Kemp JA.

Neuroscience Research Centre, Merck, Sharp & Dohme Research Laboratories, Harlow, Essex, UK.

The effect of benzodiazepines on the activity of gamma-aminobutyric acid (GABA)A receptors has been shown to be influenced by different alpha subunits and can also be affected by the presence of different gamma subunits. Previous studies have shown that receptors without a gamma subunit or those containing gamma 1 are modulated to a lesser degree by benzodiazepines. Using the Xenopus oocyte expression system to express different subunit combinations, a detailed analysis of the pharmacological modulation of GABAA receptors by various benzodiazepine site ligands has been carried out. We analyzed 14 compounds, varying through full agonist, partial agonist, antagonist, and inverse agonist, with receptors consisting of alpha 2 beta 1, alpha 2 beta 1 gamma 2S, and alpha 2 beta 1 gamma 1 and we demonstrate differences in their extent of potentiation by different benzodiazepine-type ligands. Most compounds showed negligible effects on alpha 2 beta 1 and most agonists, particularly the imidazopyridines zolpidem, alpidem, and AHR14,749, exhibited less potentiation with alpha 2 beta 1 gamma 1 than with alpha 2 beta 1 gamma 2S. The inverse agonists dimethoxy-4-ethyl-beta-carboline-3-carboxylate and Ro15-4513 did not act as inverse agonists and produced slight potentiation of alpha 2 beta 1 gamma 1 receptors. Concentration-response curves were constructed for five selected agonists to evaluate both affinity and efficacy differences between alpha 2 beta 1 gamma 2 and alpha 2 beta 1 gamma 1 receptors. Most compounds showed lower efficacy and up to 10-fold lower affinity with alpha 2 beta 1 gamma 1. Zolpidem showed slightly higher affinity but an extremely low efficacy; FG8205 also showed a markedly lower efficacy and was the most selective compound for alpha 2 beta 1 gamma 2S versus alpha 2 beta 1 gamma 1 receptors. CL218,872 showed high efficacy with alpha 2 beta 1 gamma 1 and affinity similar to that with alpha 2 beta 1 gamma 2 (being the least selective compound), suggesting that some low efficacy partial agonists with gamma 2-containing receptors may be more efficacious with gamma 1-containing receptors. The antagonists Ro15-1788 and CGS8216, although they blocked flunitrazepam potentiation of alpha 2 beta 1 gamma 2, could not block potentiation of alpha 2 beta 1 gamma 1. This study demonstrates that unique pharmacological profiles can be conferred by receptors containing different gamma subunits.

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J Chromatogr. 1993 Jun 23;616(1):95-103.
High-performance liquid chromatographic assay with diode-array detection for toxicological screening of zopiclone, zolpidem, suriclone and alpidem in human plasma.

Tracqui A, Kintz P, Mangin P.

Institut de Medecine Legale, Faculte de Medecine de Strasbourg, France.

A high-performance liquid chromatographic assay with diode-array detection has been developed for the toxicological screening of the newly developed non-benzodiazepine hypnotics and anxiolytics zopiclone, zolpidem, suriclone and alpidem. After single-step liquid-liquid extraction of plasma at pH 9.5 using chloroform-2-propanol-n-heptane (60:14:26, v/v), the substances are separated on a Nova-Pak C18 4-microns column (300 mm x 3.9 mm, I.D.), with methanol-tetrahydrofuran-pH 2.6 phosphate buffer (65:5:30, v/v) as the mobile phase (flow-rate 0.8 ml/min). Full ultraviolet spectra from 200 to 400 nm are recorded on-line during the entire analysis and may be automatically compared to spectra stored in a library. The retention times of the four drugs are 4.05 min (zopiclone), 4.66 min (zolpidem), 6.74 min (suriclone) and 10.97 min (alpidem). The analysis is performed in 15 min. The method is simple, rapid and highly specific. It is the first assay to be described for convenient screening of cyclopyrrolones and imidazopyridines.

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