Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission

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.

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A monoclonal antibody raised against a thermo-stabilised β1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of β1-adrenoceptors expressed in stable cell lines

Biochemical Pharmacology ◽

10.1016/j.bcp.2017.10.015 ◽

2018 ◽

Vol 147 ◽

pp. 38-54 ◽

Cited By ~ 3

Author(s):

Mark Soave ◽

Gabriella Cseke ◽

Catherine J. Hutchings ◽

Alastair J.H. Brown ◽

Jeanette Woolard ◽

...

Keyword(s):

Monoclonal Antibody ◽

Cell Lines ◽

Allosteric Modulator ◽

Extracellular Loop ◽

Stable Cell Lines ◽

Negative Allosteric Modulator ◽

Loop 2

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Anticonvulsant property of N-salicyloyltryptamine: evidence of enhance of central GABAergic neurotransmission

Journal of Epilepsy and Clinical Neurophysiology ◽

10.1590/s1676-26492009000400005 ◽

2009 ◽

Vol 15 (4) ◽

pp. 165-168 ◽

Cited By ~ 2

Author(s):

Lucindo J. Quintans-Júnior ◽

Davi A. Silva ◽

Jullyana S. Siqueira ◽

Adriano A.S. Araújo ◽

Adriana G. Guimarães ◽

...

Keyword(s):

Anticonvulsant Activity ◽

Receptor Complex ◽

Gabaergic Neurotransmission ◽

Gaba A ◽

Experimental Animals ◽

Anticonvulsant Property

AIM: In the present study we verified the anticonvulsant properties of the new tryptamine analogue, N-salicyloyltryptamine (NST), in rodents. METHODS AND RESULTS: In the evaluation of the anticonvulsant activity, NST protected the animals from the incidence of seizures induced by pentylenetetrazole (PTZ) and picrotoxin (PIC), in doses of 100 and 200 mg/kg. NST (100 and 200 mg/kg, i.p.) significantly eliminated the extensor reflex of maximal electric-induced seizure tests in 40% of the experimental animals. However, in the PTZ model FLU (10 mg/kg, i.p.), an antagonist of the benzodiazepine (BZD) site in the GABA A-BZD receptor complex, inhibited the prolongation of seizure latency induced by NST. CONCLUSION: Our results demonstrated an anticonvulsant activity of the new analogue that could be, at least in part, associated to the involvement of the GABAergic mechanism.

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