SBIR-STTR Award

Current treatments for alcohol abuse and dependency are marginally effective. Application of naltrexone, an opiate antagonist, appears to have only a moderate effect in reducing drinking and is not sufficiently effective in treating some sub-populations of problematic alcohol consumers or in preventing relapses. Recent attempts of using multiple drug combinations, where each individual drug addresses a different target set or neurotransmitter system, appear to improve efficacy in curtailing alcohol consumption. Concerns of multiple drug combination regimens, however, are the combined drug side effects, toxicology and pharmacokinetic issues, adding to the stress on the already stressed liver. Developing and evaluating new and more potent medications for alcoholism is still a high priority. Single agents that address multiple CNS targets may be especially attractive. The proposed Phase I research is focused on finding novel small organic molecules with modulating activities at specific membrane receptors in multiple CNS target classes. The successful execution of the proposed research will produce a suite of novel molecules that selectively modulate activity at different opiate receptor subtypes and concurrently at a specific serotonergic receptor subtype. The compounds may be used as research tools to aid in the understanding alcohol addiction and abuse, and later become the basis for therapeutics to treat alcoholism. The success of our approach will rely on the innovative integration of in silico and in vitro screening methods and large readily accessible chemical libraries. The ensuing Phase II research will focus on improving the pharmacological properties of the active compounds in order to enhance the potential for finding new and safe medications for treating alcoholism.

Thesaurus Terms:
alcoholism /alcohol abuse chemotherapy, drug design /synthesis /production, drug discovery /isolation, opioid receptor, serotonin inhibitor, serotonin receptor combinatorial chemistry, drug interaction, molecular weight, naltrexone, ondansetron, pharmacokinetics

NovaScreen Biosciences Corp. has successfully completed a Phase I SBIR project (#1 R43 AA014542-01, entitled "Novel Molecules to Treat Alcoholism") and is submitting this Phase II SBIR application in response to RFA-AA-04-002, "Medications Development to Treat Alcoholism." The specific objective of this Phase II application is to discover and to advance at least one novel, optimized, new chemical entity (NCE) up to the stage of preclinical development. That NCE will be designed to be concurrently active at multiple (two) molecular targets, each a validated drug target for treating alcoholism. Compounds active at multiple targets may have greater therapeutic efficacy than agents acting at single targets, and display fewer side effect liabilities than cocktails of two or more different drugs each active at single targets. Our Phase I SBIR research has produced a promising lead compound and an array of structure-activity relationship (SAR/QSAR) models of small molecules that concurrently modulate the serotonin 5HT3 receptor and the mu-opioid receptor. Additionally, we also produced SAR/QSAR models for compounds that display dual activity at 5HT3 and at other opioid receptor subtypes (i.e., 5HT3-delta opioid and 5HT3-kappa opioid). Our emphasis in this Phase II builds on Phase I results and employs these SAR/QSAR models to continue optimization and development of the identified lead compound to produce a new generation of therapeutic candidates for the treatment of alcohol dependency.

Thesaurus Terms:
alcoholism /alcohol abuse chemotherapy, drug design /synthesis /production, drug discovery /isolation, opioid receptor, serotonin inhibitor, serotonin receptor chemical model, combinatorial chemistry, model design /development, pharmacokinetics, receptor binding, small molecule cell line, guinea pig, laboratory mouse, laboratory rat, transfection