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.

In vitro and in vivo characterization of PheTQS, a novel α7 nAChR positive allosteric modulator

2009 ◽  
Vol 78 (7) ◽  
pp. 913 ◽  
Author(s):  
James N.C. Kew ◽  
Selina Mok ◽  
Annette Weil ◽  
Caterina Virginio ◽  
Laura Castelletti ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Α7 Nachr ◽  
In Vivo Characterization

In vitro and in vivo pharmacological characterization of SSD114, a novel GABAB positive allosteric modulator

2016 ◽  
Vol 791 ◽  
pp. 115-123 ◽  
Author(s):  
Alessandra Porcu ◽  
Carla Lobina ◽  
Daniela Giunta ◽  
Maurizio Solinas ◽  
Claudia Mugnaini ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Pharmacological Characterization

P2-311: In vitro characterization of s44858: A positive allosteric modulator of ampa receptors and GluN2B selective non-competitive nmda receptors antagonist

2015 ◽  
Vol 11 (7S_Part_13) ◽  
pp. P612-P613
Author(s):  
Laurence Danober ◽  
Jean-Yves Thomas ◽  
Sylvie Challal ◽  
Nathalie Rogez ◽  
Karine Albinet ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Ampa Receptors ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
In Vitro Characterization

Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14556-e14556
Author(s):  
J. Li ◽  
X. Sha ◽  
P. LoRusso
Keyword(s):  
Metabolic Pathway ◽  
Genetic Variants ◽  
Parp Inhibitor ◽  
Liver Microsomes ◽  
Therapeutic Outcome ◽  
Cytotoxic Agents ◽  
Wild Type ◽  
Metabolite Formation ◽  
Drug Concentrations

e14556 Background: Poly(ADP-ribose) polymerase (PARP) is essential for single-stranded DNA break repair and repair of DNA damage can lead to radio- and chemo-resistance. Thus, inhibition of PARP activity can sensitize cells to cytotoxic therapies. ABT-888 is a potent, orally bioavailable PARP inhibitor. Preclinical studies suggest that ABT-888 potentiates multiple cytotoxic agents and its efficacy is correlated with plasma/tumor drug concentrations. The objective of this study was to determine the pharmacogenetic effect of genetic variants in the ABT-888 metabolic pathway, with the aim to better understand molecular basis of the variation in ABT-888 pharmacokinetics (PK) and therapeutic outcome. Methods: The major enzymes responsible for ABT-888 metabolism were identified by in vitro metabolism studies with specific recombinant human cytochrome P450 (CYP) enzymes. The functional significance of genetic variants of the identified enzymes was assessed by examining ABT-888 metabolic kinetics by candidate variant enzymes and microsomes. The association of the functional significant genetic variants with the PK and clinical outcome is being evaluated in the context of an ongoing phase I trial in which ABT-888 is administered in combination with irinotecan in patients with advanced solid tumors. Results: ABT-888 was metabolized predominantly by human CYP2D6, to a less extent by CYP1A1, and to a negligible extent by CYP1A2, 2C9, 2C19, 3A4, and 3A5. CYP2D6*10 exhibited markedly reduced catalytic capability in ABT-888 overall metabolism and the metabolite (A-925088) formation, with in vitro maximum clearance being 31% and 5.3%, respectively, of that estimated from the wild-type CYP2D6. In human liver microsomes carrying homozygous CYP2D6*4, the rates of parent drug disappearance and metabolite formation were significantly lower than those observed in the microsomes carrying wild-type CYP2D6, P < 0.05. Conclusions: CYP2D6 is the predominant enzyme responsible for the hepatic metabolism of ABT-888. Common allelic variants CYP2D6*10 and *4 are associated with significantly reduced metabolic activity towards ABT-888. CYP2D6 polymorphisms may influence the PK and therapeutic outcome of ABT-888. Its clinical relevance remains to be determined. No significant financial relationships to disclose.

In vitro binding of a radio-labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5

Synapse ◽  
2012 ◽  
Vol 67 (3) ◽  
pp. 135-144 ◽  
Author(s):  
John R. Zysk ◽  
Nathan Spear ◽  
William Fieles ◽  
Mark M. Stein ◽  
Linda S. Sygowski ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Metabotropic Glutamate ◽  
In Vitro Binding ◽  
Vitro Binding

In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE)

2011 ◽  
Vol 61 (5-6) ◽  
pp. 957-966 ◽  
Author(s):  
Elisabetta Perdona’ ◽  
Vivian J.A. Costantini ◽  
Michela Tessari ◽  
Prisca Martinelli ◽  
Corrado Carignani ◽  
...  
Keyword(s):  
Gabab Receptor ◽  
Allosteric Modulator ◽  
The Novel ◽  
Positive Allosteric Modulator ◽  
In Vivo Characterization

In Vitro neuroprotective effects of ABT-779, a positive allosteric modulator of α7 nAChRs

2011 ◽  
Vol 82 (8) ◽  
pp. 1042
Author(s):  
Min Hu ◽  
Jinhe Li ◽  
John Malysz ◽  
Timothy A. Esbenshade ◽  
Chih-Hung Lee ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Neuroprotective Effects ◽  
Α7 Nachrs
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