5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

Phillips, Dean; Sonnenberg, Jennifer D.; Arai, Amy; Vaswani, Rishi G.; Krutzik, Peter O.; Kleisli, Thomas; Kessler, Markus; Granger, Richard; Lynch, Gary; Chamberlin, A. Richard

doi:10.1016/s0968-0896(01)00405-9

Cited by 53 publications

(44 citation statements)

References 35 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Insights into structureactivity relations for the alkyl-BTDs are discussed in greater detail elsewhere (Phillips et al, 2002). As shown there, the large gain in potency conferred by the ethyl group in D1 is close to the theoretical maximum for a hydrophobic substituent of this size, pointing to the conclusion that a major part of its surface is in contact with the receptor.…”

Section: -Alkyl-benzothiadiazide Effects On Ampa Receptors 573mentioning

confidence: 61%

“…The new compounds are derived from IDRA-21 and differ from it mainly by an alkyl substitution at the 5Ј position. A comprehensive description of syntheses and structure-activity relations is given in Phillips et al (2002), and drug names accord with those used therein.…”

Section: Resultsmentioning

confidence: 99%

“…2E) Hall et al, 1993;Kessler et al, 1996;Arai et al, 1996bArai et al, , 2000. Binding tests were therefore used together with excised patch recordings to screen and characterize the compounds developed in this project (Phillips et al, 2002). Figure 3 illustrates the typical effects of D1 on the binding of [ 3 H]fluorowillardiine (FW) (A) and [ 3 H]AMPA (B) under several commonly employed assay conditions.…”

Section: Resultsmentioning

confidence: 99%

“…It is of interest in this regard that IDRA-type compounds and cyclothiazide cannot be "connected" through conservative substitutions in the sense that compounds with intermediary structural features have little potency at AMPA receptors. Thus, introducing a norbornyl group into alkyl-BTDs at R 3 (Phillips et al, 2002) or replacing chloride at R 7 with the sulfonamide group present in cyclothiazide (Bertolino et al, 1993) caused a loss in potency. Similarly, several cyclothiazide analogs in which the norbornenyl group had been removed or replaced by other substituents were inactive at AMPA receptors (Yamada and Tang, 1993).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Some of the modifications resulted in compounds that have much greater potency than IDRA-21 and have effects on AMPA receptor kinetics that differ radically from those of cyclothiazide. A comprehensive description of the compounds that were synthesized and examined in this study is given elsewhere (Phillips et al, 2002), and some data have been presented in abstract form (Arai et al, 1999).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Effects of 5′-Alkyl-Benzothiadiazides on (R,S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses

Arai

Xia²,

Kessler³

et al. 2002

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Alkyl-substituted benzothiadiazides (BTDs) were tested for their effects on (R,S)-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. In excised patches, the 5Ј-ethyl derivative "D1" blocked the desensitization of AMPA receptor currents during prolonged application of glutamate (EC 50 , 36 M), and it slowed deactivation of responses elicited by 1-ms glutamate pulses greater than 10-fold. [3 H]Fluorowillardiine binding to rat synaptic membranes was increased by D1 by a factor of 3.6 (EC 50 , 17 M) with a Hill coefficient near 2. In hippocampal slices, the compound reversibly increased excitatory postsynaptic currents and field excitatory postsynaptic potentials (EPSPs) with thresholds around 10 M. The size of the alkyl substituent influenced both the potency and nature of the drug effect on synaptic currents: 5Ј-methyl compounds had a 2-fold greater effect on response amplitude than on response duration, whereas 5Ј-ethyl compounds like D1 caused greater increases in duration than amplitude. In tests with recombinantly expressed AMPA receptor subunits, D1 preferred the glutamate receptor (GluR) subunit GluR4 flip (0.64 M) over GluR4 flop (5.3 M); similar affinities but with smaller flip-flop differences were obtained for GluR1 through 3. These results show that D1 and congeners are significantly more potent than the parent compound IDRA-21 and that they differ in two fundamental aspects from cyclothiazide, the most widely studied BTD: 1) D1 markedly increases the agonist affinity of AMPA receptors and 2) it has immediate and large effects on field EPSPs. The large gain in potency conferred by alkyl substitution suggests that the 5Ј substituent is in intimate contact with the receptor, with the size of the substituent determining the way in which receptor kinetics is changed.

show abstract

Section: -Alkyl-benzothiadiazide Effects On Ampa Receptors 573mentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%