Biochem Pharmacol 2018 Jan 01;147:153-169. doi: 10.1016/j.bcp.2017.11.006.

Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABA A receptors.

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The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABA A receptors (GABA A Rs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ 2 γ 2S GABA A R subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABA A Rs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology. PPTQ was found to be an allosteric agonist and a PAM (ago-PAM) at human α 1 β 2 γ 2S and α 4 β 2 δ GABA A Rs, exhibiting intrinsic activity at micromolar concentrations and potentiating the GABA-evoked signaling through the receptors at concentrations down to the low-nanomolar range. Whereas PPTQ exclusively increased the potency of GABA at the α 1 β 2 γ 2S receptor, it increased both GABA potency and efficacy at α 4 β 2 δ and displayed modest potency-based preference for α 4 β 2 δ over α 1 β 2 γ 2S . In elaborate mutagenesis and competition experiments PPTQ was found to act through the same or an overlapping site as etomidate in the transmembrane β (+) /α (-) subunit interfaces, whereas it did not seem to target the other three transmembrane interfaces in the GABA A R. Finally, the PPTQ site was shown to be allosterically linked with sites targeted by neurosteroids and barbiturates but not with the high-affinity benzodiazepine site in the α 1 β 2 γ 2S receptor. In conclusion, the development of a highly potent, bioavailable GABA A R ago-PAM by subtle modifications to the methaqualone scaffold demonstrates that derivatization of this infamous drug from the past can lead to modulators with distinct functional characteristics at the receptors.

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Species referenced: Xenopus laevis
Genes referenced: pam