scholarly journals Cognitive performance effects following a single dose of the M 1 muscarinic positive allosteric modulator VU319

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Alexander C. Conley ◽  
Alexandra P. Key ◽  
Jennifer U. Blackford ◽  
Jerri M. Rook ◽  
Jeffrey Conn ◽  
...  
Keyword(s):  
Single Dose ◽  
Cognitive Performance ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Performance Effects

scholarly journals A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator

2021 ◽  
Author(s):  
Mark Walzer ◽  
Ruishan Wu ◽  
Maha Ahmad ◽  
Jon Freeman ◽  
Gary Zammit ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Single Dose ◽  
Rem Sleep ◽  
Phase 1 ◽  
Sleep Stages ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
The Impact ◽  
Gabaergic Activity ◽  
Dose Dependent

Abstract Rationale Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. Objectives This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). Methods Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. Results In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. Conclusions Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

scholarly journals Safety and pharmacokinetics of the muscarinic positive allosteric modulator VU319: A phase 1 single dose study

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Paul A. Newhouse ◽  
Alexander C. Conley ◽  
Alexandra P. Key ◽  
Jennifer U. Blackford ◽  
Jerri M. Rook ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase 1 ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Single Dose Study ◽  
Dose Study

scholarly journals 0079 A Phase 1 Single-dose Polysomnography Study Of ASP8062, A GABAB Receptor Positive Allosteric Modulator

SLEEP ◽  
2018 ◽  
Vol 41 (suppl_1) ◽  
pp. A32-A32 ◽  
Author(s):  
M Walzer ◽  
R Wu ◽  
M Ahmad ◽  
J Freeman ◽  
G Zammit ◽  
...  
Keyword(s):  
Single Dose ◽  
Gabab Receptor ◽  
Phase 1 ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator

Correction: Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2

2020 ◽  
Vol 477 (2) ◽  
pp. 459-459
Author(s):  
Lalith K. Chaganti ◽  
Shubhankar Dutta ◽  
Raja Reddy Kuppili ◽  
Mriganka Mandal ◽  
Kakoli Bose
Keyword(s):  
Serine Protease ◽  
Structural Modeling ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator

scholarly journals Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs

2019 ◽  
Vol 10 (5) ◽  
pp. 754-760 ◽  
Author(s):  
Andrew J. Harvey ◽  
Thomas D. Avery ◽  
Laurent Schaeffer ◽  
Christophe Joseph ◽  
Belinda C. Huff ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Type I ◽  
Positive Allosteric Modulator ◽  
Α7 Nachrs

scholarly journals Comparison of pregnenolone sulfate, pregnanolone and estradiol levels between patients with menstrually-related migraine and controls: an exploratory study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cecilia Rustichelli ◽  
Elisa Bellei ◽  
Stefania Bergamini ◽  
Emanuela Monari ◽  
Flavia Lo Castro ◽  
...  
Keyword(s):  
Exploratory Study ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Pregnenolone Sulfate ◽  
Menstrually Related Migraine ◽  
History Of ◽  
Estradiol Levels

Abstract Background Neurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age. Methods Thirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay. Results Serum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student’s t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R2 = 0.1369; P = 0.0482) and age (R2 = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R2 = 0.04436, P = 0.4337, linear regression analysis). Conclusion Low levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.

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