Throughout history pathological or excessive anxiety has been clearly designated as undesirable and the understanding of is origin and treatment are a major concern. The benzodiazepines employed to treat anxiety are a group of compounds with wide therapeutic application as anxiolytics, anticonvulsants, hypnotics and muscle relaxants. Although these agents are extremely important in treatment of disease states, their exact mechanism of action remains controversial. Recently it has been reported that 3-ethoxycarbonyl-Beta-carboline(2), 3-methoxycarbonyl-Beta-carboline(1), 3-t-butoxycarbonyl-Beta-carboline(3), and 3-hydroxymethyl-Beta-carboline(4) all potently inhibit [3H] diazepam binding to benzodiazepine receptors and antagonize the anticonvulsant effects of diazepam. More importantly, in contrast to the """"""""pure"""""""" benzodiazepine antagonist R015-1788, these Beta-carbolines have been shown, in our laboratories, to possess intrinsic effects of their own, opposite to those of the benzodiazepines, and the effect is different for each compound. For example, (1) was shown to be a convulsant, (2) a proconvulsant (anxiogenic in monkeys), (4) increased sleep latency, reduced total and non-REM sleep in rats without effecting convulsions, while the t-butyl ester(3) was the first Beta-carboline to exert partial agonist/antagonist activity in vivo. In this vein, different series of 3-hydroxymethyl-, 3-alkylketo-, and 3-alkoxycarbonyl-substituted Beta-carbolines will be snythesized and tested in vitro (synaptosomal membranes) and in vivo (mice, rats, monkeys) to determine what structural requiremens are necessary for potent selective, antagonist or agonist activity; the 3-alkylketo compounds are important for they cannot be metabolized to the inactive acid(5). Since the effects reported for Beta-carbolines are different from those reported for R015-1788, alkylating agents based on the structure of Beta-carbolines will be prepared to label the putative antagonist site(s) of benzodiazepine receptors and data compared to that for benzodiazepine irreversible inhibitors irazepine and kenazepine. Knowledge gained from the above experiments will: 1) result in preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether Beta-carbolines bind to the same receptor site(s) as do benzodiazepines, 3) determine whether benzodiazepine receptors are involved in the physiologic control of sleep (3HMC work), and 4) provide a better understanding of the physiological processes related to, or regulated by the benzodiazepine receptor complex. In addition, gram quantities of analogs of 1-4 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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