2017
DOI: 10.1021/acs.molpharmaceut.7b00183
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Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators

Abstract: We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α4β3γ2 GABAAR selective compound 1 and acidic α5β3γ2 selective GABAAR positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compound 1 and 2 decreased eosinophils in bronchoalveolar… Show more

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Cited by 28 publications
(54 citation statements)
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References 42 publications
(124 reference statements)
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“…Urine was collected using this method during each day during the last week of compound dosing. For MIDD0301 quantification, 100 μL of urine was combined with 400 μL methanol containing compound 2 as internal standard. The solution was centrifuged at 10 000 × g for 10 minutes and the supernatant evaporated to dryness (speedvac).…”
Section: Methodsmentioning
confidence: 99%
“…Urine was collected using this method during each day during the last week of compound dosing. For MIDD0301 quantification, 100 μL of urine was combined with 400 μL methanol containing compound 2 as internal standard. The solution was centrifuged at 10 000 × g for 10 minutes and the supernatant evaporated to dryness (speedvac).…”
Section: Methodsmentioning
confidence: 99%
“…A series of compounds that lack a pendent phenyl ring and exhibit selective α 4 β 3 γ 2 GABA A R binding was described as potential new treatments for asthma ( Figure 1 , 1 ) [ 22 , 23 , 24 ]. Among a series of more than thirty compounds, none exhibited significant KOR affinity.…”
Section: Resultsmentioning
confidence: 99%
“…[37][38][39] GABA A Rs have now been shown to have an important role in peripheral inflammatory disorders such as asthma. 40,41 It is therefore surprising that the role of GABA A Rs in major peripheral inflammatory disorders such as IBD is poorly understood, even though preliminary evidence suggests that some GABA A R ligands could prove therapeutically useful for such conditions. 13 The current study provides proof of concept that a3-GABA A Rs, in particular, play a direct role in mediating stress-induced GI inflammation, because the constitutive deletion of the GABA A R a3 subunit gene abolished stress-induced colonic inflammation (Figure 4).…”
Section: Discussionmentioning
confidence: 99%