Loop-F of the α-subunit determines the pharmacologic profile of novel competitive inhibitors of GABAA receptors

Mihalik, Balázs [Mihalik, Balázs (molekuláris farma...), szerző]; Pálvölgyi, Adrienn; Bogár, Ferenc [Bogár, Ferenc (Molekula modellezés), szerző] MTA-SZTE Szupramolekuláris és Nanoszerkezetű An... (SZTE / ÁOK / OVI); Megyeri, Katalin; Ling, István; Barkóczy, József; Bartha, Ferenc [Bartha, Ferenc (kémia), szerző] Orvosi Vegytani Intézet (SZTE / ÁOK); Martinek, Tamás A [Martinek, Tamás (Gyógyszerkémia), szerző] MTA-SZTE Lendület Peptidfoldamer Kutatócsoport (SZTE / GYTK / GYAI); Gacsályi, István; Antoni, Ferenc A [Antoni, Ferenc András (Endokrinológia), szerző]

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
  • SJR Scopus - Pharmacology: Q2
Azonosítók
Szakterületek:
    The neurotransmitter gamma-amino butyric acid (GABA) has a fundamental role in CNS function and ionotropic (GABA(A)) receptors that mediate many of the actions of GABA are important therapeutic targets. This study reports the mechanism of action of novel GABA(A) antagonists based on a tricyclic oxazolo-2,3-benzodiazepine scaffold. These compounds are orthosteric antagonists of GABA on heteropentameric GABA(A) receptors of alpha x beta 2 gamma 2 configuration expressed in HEK293 cells. In silico modelling predicted that the test compounds docked in the GABA binding-pocket and would interact with amino-acid residues in the alpha- and beta-subunit interface that are known to be important for the binding of GABA. Intriguingly, optimal docking also required an interaction with the non-conserved amino-terminal segment of Loop-F of the alpha-subunit. Testing of a compound with altered regiochemistry of the oxazolone moiety supported the model with respect to the conserved GABA-interacting residues in vitro as well as in vivo. The prediction regarding, loop-F was examined by replacing the amino-terminal variable segment of loop-F of the alpha 5-subunit with the corresponding residues in the alpha 1- and alpha 2 subunits. When tested with the novel inhibitors, the receptors formed by the modified alpha 5-subunits displayed the pharmacologic phenotype of the source of loop-F. In summary, these data show that the variable amino terminal segment of loop-F of the alpha-subunit determines the pharmacologic selectivity of the novel tricyclic inhibitors of GABA(A) receptors.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSL
    2019-09-18 11:26