Enhancing glutamate (Glu) uptake by positive allosteric modulation of excitatory amino acid transporter subtype 2 (EAAT2) is an attractive strategy to enable neuroprotection. However, while the EAAT field is rich in reports on inhibitors, enhancing EAAT2 protein dynamics is a much more difficult objective. A natural product approach reported that a spider venom HPLC fraction, number 10, showed neuroprotective effects. It was referred to as parawixin10, and later the structure of the key component responsible for the neuroprotective action was disclosed to be an N-acylamine, compound 2. We have resynthesized the N-acylamine 2 (parawixin10) and show here that this compound does not enhance Glu uptake in a wide range of radioligand binding assays, nor does it, in our hands, show any neuroprotective effect in a dose-dependent, statistically significant way.
Doroudian et al. (2026) studied this question.