Selective CB1 cannabinoid receptor ligands have therapeutic potential for various medical conditions, including obesity, substance (e.g. nicotine) abuse disorders, pain, inflammation, cancer, and cardiometabolic diseases. Currently, there is considerable interest in the therapeutic use of CB1 antagonists resulting from the recent approval in Europe of rimonabant (AcompliaTM, SR141716A), a CB1 antagonist. Rimonabant has also demonstrated efficacy in smoking-cessation therapy. While generally well tolerated, there was nonetheless a high dropout rate and an increased incidence of nausea and psychiatric disorders associated with rimonabant clinical trials, highlighting the need to develop safer alternatives. Developing a CB1 antagonist with a different pharmacological mechanism may represent a safer alternative. A promising alternative approach is the development of negative allosteric modulators of CB1 receptors which, by binding to a sub-type-specific and topographically distinct site from the orthosteric pocket, would inhibit the action of endocannabinoids and thus act more selectively to tune CB signaling in a site- and event-specific fashion. This approach has the potential to identify highly-selective compounds with a minimal propensity to produce adverse effects. Recently, high throughput screening from different research groups has identified two classes of ligands exhibiting allosteric antagonism at the CB1 receptor. Significant structural similarity was observed among these hits. The primary goal of this project is to develop high affinity, potent and efficacious allosteric modulators of the CB1 receptor, based on the structure of the current lead PSNCBAM-1, which will be devoid of adverse side effects. The proposed structural variations are aimed at improving affinity, potency, and physicochemical properties of the parent lead. Newly synthesized allosteric modulators will be evaluated for their ability to modulate the binding of the orthosteric ligands [3H]CP55,940 and [3H]SR141716A. A select group of novel compounds exhibiting promising results will be evaluated in a [35S]GTP3S binding assay to define their functional potency. 'Successful ligands'will be evaluated in mouse for their in vivo blood plasma and brain concentrations (BBB penetrability) following intravenous dosing utilizing quantitative LC/MS analysis. We expect that our effort will lead to the identification of "potential drug candidates" which will be evaluated subsequently in non-human primates. PUBLIC HEALTH RELEVANCE: Endocannabinoids regulate many processes in health and disease by acting through cell receptors. Modulators of endocannabinoid activity hold therapeutic promise for a wide range of medical problems, including mood and anxiety disorders, Parkinson's and Huntington's diseases, pain, multiple sclerosis, cancer, cardiovascular disease, obesity, and osteoporosis. Molecules that modify the action of cannabinoid receptors offer a new, potentially very safe approach for drugs to treat these and other diseases.
NIH ExPorter
NIH ExPorter