Neuroactive steroids are becoming increasingly important in neurobiology and alcoholism. Several neurosteroids have recently been shown to have alcohol-like actions in behavioral tests, and to modulate neurotransmitter systems which are thought to be the key to the development of alcohol dependence. The purpose of this Phase I feasibility study is to develop a mechanism for providing multigram quantities of neuroactive steroids and synthetic analogs for research and clinical application. Currently available commercial sources of neuroactive steroids are very expensive and of limited purity. The proposed experiments will be directed at streamlining synthesis, improving purity, and developing new synthetic analogs of neuroactive steroids which possess more effective biological activity by optimizing new procedures for synthesis and purification, and by exploring new chemical pathways. The objectives under Phase I are to: (1) Develop more effective synthesis of endogenous neurosteroids; (2) Purify these products beyond the level of purity commercially available at present; (3) Produce synthetic steroids that are analogs of endogenous compounds, and; (4) Evaluate the biological activity of a selected number of new products. Once these Phase I objectives are met, the products will then be made commercially available for research purposes to establish their efficacy in animal models of alcohol dependence and relapse (Phase II). The long-term commercial objective of this proposal will be to provide medication for the treatment of alcoholism and its vulnerability to relapse.
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