Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABAA receptors

Madjroh, Nawid; Olander, Emma Rie; Bundgaard, Christoffer; Söderhielm, Pella Cecilia; Jensen, Anders A.

doi:10.1016/j.bcp.2017.11.006

Cited by 6 publications

(31 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Irrespective of our binding site hypothesis, our novel analogs of DS2 show that the 5-position of the scaffold is clearly vital for the pharmacological profile of the analogs (PAM/ago-PAM) as well as for the preference for α 4 β 1 δ vs. α 4 β 1 γ 2 . Such dual activity is a known phenomenon, 41 where subtle structural differences result in diverse pharmacological activity profiles and selectivity as previously reported within the cys-loop receptor research field 42,43 .…”

Section: Structural Rationalization Of Major Sar Observationsmentioning

confidence: 68%

“…The compounds 27, 29, and 34 were found to have no activity at α 4 β 1 δ and were therefore not pursued further. In addition, the poor solubility of the 1,2,4-oxadiazole (42) precluded the compound from pharmacological characterization. Compounds 24-26 and 33 demonstrated agonist activity as these compounds induced responses at α 4 β 1 δ in the absence of GABA, making these compounds ago-PAMs.…”

Section: Scheme 4 Synthesis Of Amide Bioisosteres Of Ds2mentioning

confidence: 99%

See 1 more Smart Citation

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Frølund

Rostrup²,

Falk-Petersen³

et al. 2020

Preprint

View full text Add to dashboard Cite

<div>A SAR study of the delta-selective positive modulators DS2 was performed to assist the quest for the binding site. The modulatory effect was measured using a fluorometric inaging plate reader (FLIPR) membrane potential (FMP) functional assay. Specific positions in the structural scaffold of DS2 was found to severly affect the pharmacological profile. <br></div><div>Analogs superior to DS2 were identified displaying higher potency and selectivity for the alfa4beta1delta over alfa4beta1gamma.<br></div><br>

show abstract

Section: Structural Rationalization Of Major Sar Observationsmentioning

confidence: 68%

Section: Scheme 4 Synthesis Of Amide Bioisosteres Of Ds2mentioning

confidence: 99%

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Frølund

Rostrup²,

Falk-Petersen³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Irrespective of our binding site hypothesis, our novel analogues of DS2 show that the 5-position of the scaffold is clearly vital for the pharmacological profile of the analogues (PAM/ago-PAM) as well as for the preference for α4β1δ versus α4β1γ2. Such dual activity is a known phenomenon, where subtle structural differences result in diverse pharmacological activity profiles and selectivity as previously reported within the cys-loop receptor research field. , …”

Section: Resultsmentioning

confidence: 70%

“…The compounds 27, 29, and 34 were found to have no activity at α4β1δ and were therefore not pursued further. In addition, the poor solubility of the 1,2,4-oxadiazole (42) precluded the compound from pharmacological characterization. Compounds 24−26 and 33 demonstrated agonist activity as these compounds induced responses at α4β1δ in the absence of GABA, making these compounds ago-PAMs.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Such dual activity is a known phenomenon, 41 where subtle structural differences result in diverse pharmacological activity profiles and selectivity as previously reported within the cys-loop receptor research field. 42,43 ■ CONCLUSIONS In summary, we have synthesized a series of novel DS2 analogues through complementary synthesis strategies allowing structural diversification of the imidazopyridine core scaffold and identified novel compounds with better potency at, and higher selectivity for, δ-containing GABA A Rs. We find that substituents in the 5-position of the imidazopyridine core scaffold severely affect both the δ-selectivity and modulatory activity.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

Rostrup

Falk-Petersen

et al. 2021

J. Med. Chem.

View full text Add to dashboard Cite

Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.

show abstract

Delineation of the functional properties and the mechanism of action of AA29504, an allosteric agonist and positive allosteric modulator of GABAA receptors

Olander

Madjroh

Bunch

et al. 2018

Biochemical Pharmacology

View full text Add to dashboard Cite

The retigabine analog 2-amino-4-[(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) is a positive allosteric modulator (PAM) of γ-aminobutyric acid receptors (GABARs), and the modulator has been used in ex vivo/in vivo studies to probe the physiological roles of native δ-containing GABARs. In this study, the functional properties and mode of action of AA29504 were investigated at human GABARs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology. AA29504 was found to be an allosteric GABAR agonist displaying low intrinsic activities at 3-30 μM. AA29504 was essentially equipotent as a PAM at the 13 GABAR subtypes tested (EC: 0.45-5.2 μM), however GABA EC-evoked currents through αβδ subtypes were modulated to substantially higher levels than those through αβγ subtypes (relative to GABA I). While the δ/γ-difference clearly was key for this differential GABA efficacy modulation, studies of the AA29504-mediated modulation of different α-containing αβ, αβγ and αβδ GABARs revealed the α-subunit identity to be another important determinant. Based on its functional properties at numerous mutant GABARs and on in silico analysis of its low-energy conformations, AA29504 is proposed to act through an allosteric site in the transmembrane β/α interface in the GABAR also targeted by etomidate and several other modulators. In contrast to these modulators, however, AA29504 did not display substantial β/β-over-β GABAR preference, which challenges the notion of ligands targeting this site always possessing this subtype-selectivity profile. Hence, the detailed pharmacological profiling of AA29504 both highlights the complexity of allosteric GABAR modulation and provides valuable information about this modulator as a pharmacological tool.

show abstract

Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABAA receptors

Cited by 6 publications

References 57 publications

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

Delineation of the functional properties and the mechanism of action of AA29504, an allosteric agonist and positive allosteric modulator of GABAA receptors

Contact Info

Product

Resources

About