Towards functional selectivity for α6ß3γ2 GABAA receptors: a series of novel pyrazoloquinolinones.
Br J Pharmacol
; 175(3): 419-428, 2018 02.
Article
in En
| MEDLINE
| ID: mdl-29127702
ABSTRACT
BACKGROUND AND PURPOSE:
The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/ß- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTALAPPROACH:
Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method. KEYRESULTS:
We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6ß3γ2 GABAA receptors with nearly no residual activity at the other αxß3γ2 (x = 1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/ß- interfaces. CONCLUSION AND IMPLICATIONS These results constitute a major step towards a potential selective positive modulation of certain α6-containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Receptors, GABA-A
/
Quinolones
/
GABA Modulators
Limits:
Animals
Language:
En
Journal:
Br J Pharmacol
Year:
2018
Document type:
Article
Affiliation country: