Recent reports suggest that GABAA receptors (GABAAR) which contain the α6 subunit are found primarily in the granule cells of the cerebellum and the olfactory bulb. It has been reported that α6β2/3γ2 subtype selective ligands may be important in the treatment of trigeminal orofacial pain, neuropsychiatric disorders with sensori-motor gating deficits (such as tic disorders, certain symptoms of schizophrenia, obsessive compulsive disorder and attention deficit disorders), and depression, as well as migraine. Included in this report are the first in vitro metabolic and cytotoxicity studies as well as an in vivo assessment of locomotion, pharmacokinetic and other in vivo data on these functionally selective α6β2/3γ2 GABAAR ligands. In order to increase the duration of action of analogs, deuteration of the methoxy group of aryl-pyrazoloquinolinones herein has been shown to improve the metabolic stability and bioavailability (via both oral and intraperitoneal administration) of these ligands, while their selectivity for the GABAAR α6 subtype was retained. Of a series of 45 analogs synthesized, DK-I-56-1 was identified as the lead compound with a substantially improved pharmacokinetic profile for further examination in behavioral and disease models to better understand the function of the GABAAR α6β2/3γ2 subtypes in physiological processes. In addition to expanding the SAR of functionally selective α6β2/3γ2 GABAAR ligands, these diazepam insensitive (DI) ligands were found to be non-sedating in contrast to diazepam sensitive (DS) benzodiazepines (diazepam, alprazolam, etc). Moreover, these analogs were not cytotoxic, two properties of which, render them potential candidates for treatment of CNS disorders described above associated with the GABAAR α6β2/3γ2 subtypes.

Design and synthesis of novel deuterated GABAAR-α6 subtype selective ligands with improved metabolic stability and enhanced bioavailability

255th National Meeting (2018)

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