SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS

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DESCRIPTION (Adapted from applicant's abstract): The understanding and treatment of pathological anxiety including panic disorder have long been a prime concern in regard to mental health. In a recent study it was reported, people who suffer panic disorder or panic attacks are as likely to contemplate or attempt suicide as patients with other mental disorders such as major depression. From 3-10% of the adult population suffer from panic attacks during their lives. The benzodiazepines (Bz) used to treat these diseases have been shown to exhibit a broad spectrum of pharmacologic efficacies including anticonvulsant, sedative-hypnotic, muscle-relaxant and anxiolytic effects (2-11). Despite the clinical effectiveness of these drugs, there is a need for selective anxiolytic/anticonvulsants (10-12) which are devoid of the myorelaxant/ataxic and sedative side effects of the benzodiazepines. In this regard recent results (14, 20) from our laboratory are exciting. Based on a chemical and computer-assisted analysis of the inclusive pharmacophore for the BzR, the pharmacophoric descriptors for agonist versus inverse antagonist have been defined. More importantly, the 8-acetylenic substituted imidazobenzodiazepines 1a and 2a have been shown to be 40-70 times more selective for Bz5 (alpha5beta2gamma2) receptor subtypes, while betaCCt 5 has been shown to be 20 times more selective for Bz1 (alpha1beta2gamma2) receptor subtypes. These are the most selective ligands ever reported for alpha5 and alpha1 BzR subtypes, respectively, and serve as lead compounds in the search for BzR subtype specific agents. Rigid and semi-rigid (constrained) ligands will be employed to develop agents selective for Bz1 (Schemes 7,8,9 and 12), and Bz5 (Schemes 4,5,6,10 and 11) receptor subtypes. The goal is to develop ligands that are more than 150 times more selective for either Bz1 or Bz5 receptor subtypes in order to determine which biological function(s) is mediated by which subtype. It is felt that Bz subtype selective agents provide one of the best opportunities to develop anxioselective anxiolytic and anticonvulsants devoid of side effects and to understand the complex physiological processes mediated by the GABA/BzR receptor ion channel. Once selective ligands for these sites are developed, Bz2 (alpha2) and Bz3 (alpha3) as well as Bz4 (D1) alpha4 and Bz6 (D1) alpha6 receptor subtypes will be investigated. Characterization of the pharmacology of BzR receptors at the subtype level is crucial for understanding the physiological processes which underlie anxiety, including panic disorder convulsions, and sleep disorders as well as the design of selective agents (agonists) to treat these disease states with decreased abuse potential.