Arai AC, Xia YF, Kessler M, Phillips D, Chamberlin R, Granger R, Lynch G (2002). Effects of 5'-Alklyl-Benzothiadiazides on AMPA... Molecular Pharmacology, 566-577.

Arai A, Yan-Fang X, Kessler M, Phillips D, Chamberlin R, Granger R, Lynch G.


AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 mM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 50 -position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 50 -ethyl derivative exhibited an EC50 value in the order of 22 mM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC50 value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 50 -ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure–activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor–drug interactions.

Richard Granger