Structural features of phenol derivatives determining potency for activation of chloride currents via α1 homomeric and α1β heteromeric glycine receptors

Abstract

Phenol derivatives constitute a family of neuroactive compounds. The aim of our study was to identify structural features that determine their modulatory effects at glycine receptors. We investigated the effects of four methylated phenol derivatives and two halogenated analogues on chloride inward currents via rat alpha(1) and alpha(1)beta glycine receptors, heterologously expressed in HEK 293. All compounds potentiated the effect of a submaximal glycine concentration in both alpha(1) homomeric and alpha(1)beta glycine receptors. While the degree of maximum potentiation of the glycine 10 microM effect in alpha(1)beta receptors was not different between the compounds, the halogenated compounds achieved half-maximum potentiating effects in the low microM range -- at more than 20-fold lower concentrations compared with their nonhalogenated analogues (P<0.0001). The coactivating effect was over-ridden by inhibitory effects at concentrations >300 microM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC(50) for coactivation. Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 microM) directly activated both alpha(1) and alpha(1)beta receptors up to 30% of the maximum response evoked by 1000 microM glycine. These results show that halogenation in the para position is a crucial structural feature for the potency of a phenolic compound to positively modulate glycine receptor function, while direct activation is only seen with high concentrations of compounds that carry at least two methyl groups. The presence of the beta subunit is not required for both effects.