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D18A0004

Novel GABAAR-a6 Subtype-selective Ligands for Neuropsychiatric disorders

Project Description
The team provide pyrazoloquinolinones, which are are highly selective positive allosteric modulators of GABAA receptors containing alpha 6 subunits.  Unexpectedly, they can rescue disrupted prepulse inhibition (PPI) that is an endophenotype manifestation present in several neuropsychiatric disorders, such as schizophrenia, tic disorders/Tourette syndrome, schizophrenia, obsessive-compulsive disorder, attention deficit disorder, mania in bipolar disorder, panic disorder, nocturnal enuresis, antisocial personality disorderHuntington´s disease, premenstrual dysphoric disorder, mania in bipolar disorder, and Huntington´s disease antisocial personality disor.  The developed pyrazoloquinolinones also shown their capbilities in reducing trigeminal neuropathic pain in rats through the capsaicin-induced trigeminal neuronal activation in the trigeminal vascular system (TGVS) in an animal model.  Of a series of 42 novel analogs synthesized, compounds DK-I-56-1 and PZ-II-029 were identified as the lead compounds with a substantially improved pharmacokinetic profile.  The team further studied the muscle incoordinating and cytotoxic properties for this family of ligands so as to make The developed pyrazoloquinolinones ideal candidates for CNS drug development.

Intellectual Property
PCT application submitted in 2016.

 
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