The understanding and treatment of pathological anxiety including panic disorders (14) 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 to 10% of the adult population suffer from panic attacks during their lives. The benzodiazepines (BzR) used to treat these diseases have been shown to exhibit a broad spectrum of pharmacologic efficacies including anticonvulsant (27), sedative-hypnotic (27), muscle-relaxant (28), and anxiolytic/-anticonvulsants (13) which are devoid of the myorelaxant- sedative side effects of the benzodiazepines.(13,20,27,28). It is conceivable that these anxioselective anxiolytics might also exhibit decreased abuse potential, as well as reduced symptoms of withdrawal. In this regard, recent results(15,16) from our laboratory are exciting. A chemical and computer assisted analysis of the pharmacophore for agonists at the BzR has been executed(15). Based on this model the 6- propyl ether (6 PBC) (16) has been synthesized and screened in mice. This new agent was found to elicit anxiolytic/anticonvulsant activity, but was completely devoid (16) of the muscle relaxant/ataxic effects which occur with the benzodiazepines. More importantly, 6 PBC (16) completely antagonized the muscle relaxant effects of diazepam while still producing the anxiolytic effect. Outlined in Schemes III-IX are rigid and semi-rigid ligands which will be prepared to define the exact spatial dimensions of the agonist binding domain (see Figures 4-8) at lipophilic regions, as well as the importance of electron density on the ligands at phi 1 and phi 2. These agents will be synthesized and then tested in vitro and in vivo (mice/rats) for their efficacy. The biological data and SAR will be programmed into the E/S-390 (SYBYL) system to further define the pharmacophore for agonists. Since the principle goal is the synthesis of selective anxiolytic/anticonvulsants, the spatial dimensions and electron density required for selective agonist activity will be determined. This would constitute a real step forward in the search for selective anxiolytics. By the very nature of the computer-assisted design of the ligands depicted in Schemes III-IX, many of these bases will exhibit agonist activity; our principal interest lies in those which elicit a selective agonist profile of activity. CoMFA analysis (17,18) will be executed on these latter analogs whenever the SAR/biology is available. Characterization of the BzR at the molecular level is crucial for understanding the biochemical mechanisms which underlie anxiety (29), including panic disorders (14), and convulsions 27, as well as the design of selective agents (agonists) to treat these disease states. It is believed, the successful execution of the above studies will have far reaching effects in medicinal chemistry and neurobiology.
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