Selective Anxiolytics via BzR Subtype Specific Ligands

University Of Wisconsin Milwaukee, Milwaukee WI

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Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): A number of a2B3y2, a2B3y2/a3B3y2 and a5B3y2 subtype selective ligands for the BzR/GABAA receptor have been prepared. Many of these have 200-fold or better selectivity for one subtype over another and are important tools to determine what physiological function(s) is subserved by each receptor subtype. The therapeutic potential of these agents against anxiety disorders, epilepsy, cognition deficits and alcohol abuse is enormous. They are orally active and safe in most cases. Unfortunately, receptor binding studies for receptor subtype selectivity by our Merck collaborators has ended abruptly (without notice), and over 130 ligands from excellent leads are in hand which require Ki values at the six BzR/GABA subtypes. This supplement is requested solely for funds to set up a subcontract with Dr. Bryan Roth at Case Western Reserve University to clone/express the BzR/GABA receptors and execute the binding on these 130 ligands and about 200 more each year for several years, if need be. The group at Case already screens ligands for NIH-supported investigators at over 20 different neuroreceptors and a corollary to this work will provide this NIMH funded screening program for a(1-6) B3y2 BzR/GABA receptors to everyone, not just to our group. These Ki values determined at Case Western Reserve University will be invaluable in the design of new nonsedating anxiolytics for a host of anxiety disorders as well as (GABA(a1) antagonists to treat alcohol abuse per our original goals [unreadable] [unreadable]