scholarly journals Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5‐Subtype Selective GABA A ‐Positive Allosteric Modulator PF‐06372865 in Healthy Volunteers

2021 ◽  
Author(s):  
Rachel Gurrell ◽  
Mark Whitlock ◽  
Hua Wei ◽  
Zhongzhou Shen ◽  
Adam Ogden
Keyword(s):  
Healthy Volunteers ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Gaba A ◽  
Subtype Selective ◽  
Oral Doses

scholarly journals AZD-3043

2012 ◽  
Vol 116 (6) ◽  
pp. 1267-1277 ◽  
Author(s):  
Talmage D. Egan ◽  
Shinju Obara ◽  
Thomas E. Jenkins ◽  
Sarah S. Jaw-Tsai ◽  
Shanti Amagasu ◽  
...  
Keyword(s):  
Dynamic Model ◽  
Metabolic Pathway ◽  
Liver Microsomes ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Duration Of Action ◽  
Chloride Currents ◽  
Gaba A ◽  
Hypnotic Agent

Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. Methods The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.

scholarly journals Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAAReceptor Positive Allosteric Modulator

2017 ◽  
Vol 8 (6) ◽  
pp. 1305-1312 ◽  
Author(s):  
Lakeisha A. Lewter ◽  
Janet L. Fisher ◽  
Justin N. Siemian ◽  
Kashi Reddy Methuku ◽  
Michael M. Poe ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Antinociceptive Effects ◽  
Subtype Selective

scholarly journals Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats

2019 ◽  
Vol 30 (5) ◽  
pp. 452-461 ◽  
Author(s):  
Megan J. Moerke ◽  
Guanguan Li ◽  
Lalit K. Golani ◽  
James Cook ◽  
S. Stevens Negus
Keyword(s):  
Gabaa Receptor ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Subtype Selective

scholarly journals Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model

2018 ◽  
Vol 25 (2) ◽  
pp. 255-260 ◽  
Author(s):  
Venceslas Duveau ◽  
Derek L. Buhl ◽  
Alexis Evrard ◽  
Céline Ruggiero ◽  
Betty Mandé-Niedergang ◽  
...  
Keyword(s):  
Absence Epilepsy ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Antiepileptic Activity ◽  
Subtype Selective

scholarly journals Announcing the novel class of GABA–A receptor selective positive allosteric modulator antidepressants

2021 ◽  
Vol 7 (2) ◽  
pp. FSO654
Author(s):  
Olumuyiwa John Fasipe ◽  
Olalekan Ayodele Agede ◽  
Adenike Christiana Enikuomehin
Keyword(s):  
Allosteric Modulator ◽  
The Novel ◽  
Positive Allosteric Modulator ◽  
Gaba A

A Novel Peripherally Restricted GABA-a Positive Allosteric Modulator Shows Efficacy in a Model of Irritable Bowel Syndrome

2017 ◽  
Vol 152 (5) ◽  
pp. S181
Author(s):  
Qian Li ◽  
Yifang Huang ◽  
Nicholas E. Calcaterra ◽  
James C. Barrow ◽  
Pankaj J. Pasricha
Keyword(s):  
Irritable Bowel Syndrome ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Gaba A ◽  
Irritable Bowel
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