Throughout history pathological or excessive anxiety has been clearly designated as undesirable and the understanding of its origin and treatment are a major concern. The benzodiazepines (Bz) employed to treat anxiety are a group of compounds with wide therapeutic applications as anxiolytics, anticonvulsants, hypnotics and muscle relaxants 6,7. These agents are now felt to exert their physiological effects via the GABA/Bz/C1 complex 2,45. Recently, a series of rigid, planar dihydropyridodiindoles have been synthesized in our laboratory and shown to demonstrate potent affinity (5 nM) for benzodiazepine receptors (BzR) in vitro 17. The parent compound 2 (X=H) exhibited inverse agonist activity in vivo 17. Moreover, the 2-methoxy analog 4e was a potent proconvulsant, while the 2-chloro analog 4d demonstrated antagonist activity 17 similar to Ro 15-1788. It is felt these rigid analogs may conform to one receptor subsite, but will not be able to rotate, conformationally 21,61, to bind to a second subtype. In addition to enhanced Bz1 or Bz2 selectivity, these rigid planar, active ligands will be employed to model the pharmacophore for BzR. Based on these leads, different series of rigid 4, 7, 10, and semirigid 8, 9 analogs will be synthesized and tested in vitro (synaptosomal membranes) and in vivo (mice, rats, monkeys) to determine what structural requirements are necessary for potent selective (Bz1, or Bz2) inverse agonist, antagonist or agonist activity; the pyridodiinodoles 4 are important for they should possess long half-lives in vivo. Since the effects observed for beta-carbolines 12, 2 and 4e17 are different from those reported for Ro 15-1788 15, irreversible inhibitors based on these beta- carboline analogs will be prepared to label the """"""""proposed"""""""" 32,59,60 discrete inverse agonist/antagonist receptor site. Information gained from the above studies will: 1) result in preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether or not beta-carbolines bind to the same receptor sites(s) as do benzodiazepines, 3) determine the effect of benzodiazepine receptors on anxiety 4,9,22,23, sleep, 28 conclusions 27, and memory 29 by providing a better understanding of the physiological processes influenced by the GABA/Bz/C1 complex 2, 45. In addition, gram quantities of analogs related to 4, 7, 8, 9, and 10 will be prepared and screened in vivo to separate out the intrinsic effects of beta-carbolines, and to design agents specific for interaction with one Bz receptor subtype in preference to another.

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National Institute of Mental Health (NIMH)
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University of Wisconsin Milwaukee
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