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  • 1
    Electronic Resource
    Electronic Resource
    Formation of d-Serine from l-Phosphoserine in Brain Synaptosomes (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Although glycine has been assumed to be the sole endogenous coagonist at NMDA-associated glycine receptors, recent descriptions of endogenous d-serine in the brain indicate that this assumption is probably not valid. d-Serine is a stereospecific agonist of the NMDA-associated glycine receptor, with an affinity equal to or greater than that of glycine but with no affinity for the strychnine-sensitive glycine receptor. In the current studies, we assessed the levels and metabolic sources of d-serine in rat neocortical synaptosomal preparations. Previous studies have demonstrated that CNS serine and glycine are synthesized de novo primarily via a phosphorylated pathway, originating with the glycolytic intermediate phosphoglycerate. The rate-limiting step in the synthesis of serine is the hydrolysis of phosphoserine by phosphoserine phosphatase (EC 3.1.3.3). In synaptosomal preparations we have demonstrated high endogenous levels of d-serine and the uptake of l-phosphoserine along with its hydrolysis to both l-serine and d-serine, which are preferentially released into the medium. Experiments with both intact and lysed synaptosomal preparations demonstrated hydrolysis of d-phosphoserine to only d-serine and inhibition of hydrolysis by the phosphoserine phosphatase inhibitor 2-amino-3-phosphonopropionic acid (AP3). The lack of stereospecificity for synaptosomal hydrolysis of phosphoserine and the inhibitory actions of AP3 are consistent with the presence of phosphoserine phosphatase in synaptosomes and further indicate that epimerization of serine can occur during or subsequent to the hydrolysis of l-phosphoserine but not d-phosphoserine. In conclusion, these studies demonstrate that phosphoserine phosphatase may be an important enzyme in regulating the steady-state levels of d-serine in neocortical synaptosomes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67041485.x
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  • 2
    Electronic Resource
    Electronic Resource
    Photoactivatable 2-[(4'-azido)tetrafluorophenyl]-5-tert-butyl-1,3-dithiane bissulfone and related compounds as candidate irreversible probes for the GABA-gated chloride channels (1994)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 37 (1994), S. 133-140 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00027a016
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593 (1997)
    Springer
    Psychopharmacology 134 (1997), S. 46-54 
    Details
    ISSN: 1432-2072
    Keywords: Key words Neurosteroid ; Neuroactive steroid ; Anxiolytic ; Anticonvulsant ; GABAA receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Endogeneously occurring neuroactive steroids, metabolites of progesterone and deoxycorticosterone, have been shown previously to interact with the GABAA receptor with great specificity in vitro and to have anticonvulsant, anxiolytic and sedative activity in vivo. However, these endogenously occurring steroids are not useful as therapeutic agents due to their potential metabolism to hormonally active steroids and their poor oral bioavailability. In an attempt to develop therapeutic agents which would maintain the pharmacological profiles of endogeneous neuroactive steroids but with increased oral bioavailability and reduced metabolic liability, we explored simple substitutions at the 3β-position of the endogenous neuroactive steroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-P). This report describes part of the in vitro and in vivo pharmacological profile of a 3β-substituted analog, 3β-ethenyl-3α-hydroxy-5α-pregnan-20-one (Co 3-0593). The compound exhibited anticonvulsant activity against pentylenetrazol-induced seizures in mice and rats (ED50 = 5.6 and 11. 5 mg/kg, IP, respectively). Co 3-0593 showed robust anxiolytic effects, comparable to benzodiazepines in the Geller-Seifter test after both SC and oral administration. Furthermore, the anxiolytic activity was maintained after chronic administration suggesting an absence of tolerance. The compound did not affect the acquisition of a learned response at both anticonvulsant and anxiolytic doses. However, at higher doses the compound showed roto-rod deficit which was further enhanced by ethanol. In summary, 3β-ethenyl-substituted 3α,5α-P appeared to maintain the pharmacological activities of the endogenous neuroactive steroid with apparent oral activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050424
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  • 4
    Electronic Resource
    Electronic Resource
    In Vitro and In Vivo Activity of 16,17-dehydro-epipregnanolones: 17,20-Bond Torsional Energy Analysis and D-ring Conformation (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1488-1494 
    Details
    ISSN: 1573-904X
    Keywords: neuroactive steroid ; epalon ; γ-aminobutyric acidA or GABAA receptor ; 3α-hydroxy-5β-pregnan-20-one ; 3α-hydroxy-5α-pregnan-20-one ; TBPS or t-butylbicyclophosphorothionate ; anesthetic ; anticonvulsant ; sedative ; alphaxalone ; pregnanolone ; molecular mechanics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Certain neuroactive pregnane steroids (also known as “epalons”) are allosteric modulators of the GABAA receptor and have been shown to be potent anticonvulsants, anxiolytics, sedative/hypnotics, and anesthetic agents. The purpose of this study was to calculate the structural consequences of introduction of a double bond in the 16,17-position and to determine if this modification would selectively reduce sedative activity, but maintain the potent anticonvulsant activity of neuroactive steroids. Methods. We have studied the biochemical and behavioral effects of introducing a 16,17 double bond into the naturally occurring neuroactive steroids, 3α-hydroxy-5α-pregnan-20-one (3α,5α-P) and 3α-hydroxy-5β-pregnan-20-one (3α,5β-P) and three synthetic neuroactive steroid derivatives, 3α-hydroxy-3β-methyl-5α-pregnan-20-one (3α,3βMe,5α-P), 3α-hydroxy-5α-androstane (3α,5α-A), and alphaxalone (3α,5α-11-one-P). Results. The 16-ene analogs of most of these neuroactive steroids were found to be 7- and 16-fold less potent in inhibiting [35S]TBPS binding to GABAA receptors and in a similar fashion, had reduced anticonvulsant and sedative potency in proportional amounts. The exception was the androstane (3α,5α-A) without a 17-acetyl group, that had virtually identical IC50 and ED50 values for the saturated and unsaturated derivatives. Calculation of the torsional energy profile for each of the 17-acetyl side chain conformations showed that the conformational energy minima found in the α,β-unsaturated keto systems, produce an orientation of the 20-keto group that is rotated by 165 degrees when compared to the non-conjugated acetyl group (determined by X-ray crystallography and its minimum energy conformation). Conclusions. The modified orientation of the 20-keto group of neuroactive steroids containing a 16-ene, provides an explanation for their decreased biological activity overall, but did not lead to an enhanced protective index.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016019327120
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    Paper (German National Licenses)
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