Article date: August 2005
By: Gertrud Haeseler, Jörg Ahrens, Klaus Krampfl, Johannes Bufler, Reinhard Dengler, Hartmut Hecker, Jeffrey K Aronson, Martin Leuwer in Volume 145, Issue 7, pages 916-925
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 α1 and α1β glycine receptors, heterologously expressed in HEK 293.
All compounds potentiated the effect of a submaximal glycine concentration in both α1 homomeric and α1β glycine receptors. While the degree of maximum potentiation of the glycine 10 μM effect in α1β receptors was not different between the compounds, the halogenated compounds achieved half‐maximum potentiating effects in the low μM 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 μM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC50 for coactivation.
Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 μM) directly activated both α1 and α1β receptors up to 30% of the maximum response evoked by 1000 μM 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 β subunit is not required for both effects.
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 α1 and α1β glycine receptors, heterologously expressed in HEK 293.
All compounds potentiated the effect of a submaximal glycine concentration in both α1 homomeric and α1β glycine receptors. While the degree of maximum potentiation of the glycine 10 μM effect in α1β receptors was not different between the compounds, the halogenated compounds achieved half‐maximum potentiating effects in the low μM 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 μM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC50 for coactivation.
Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 μM) directly activated both α1 and α1β receptors up to 30% of the maximum response evoked by 1000 μM 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 β subunit is not required for both effects.
British Journal of Pharmacology (2005) 145, 916–925. doi:10.1038/sj.bjp.0706254
DOI: 10.1038/sj.bjp.0706254
View this article