The actions of acamprosate, memantine and mecamylamine in alcohol dependence suggest that glutamate receptors (specifically NMDARs and mGluRSs) and acetylcholine receptors (specifically nicAChRs) are potential molecular targets for prevention of relapse. Many natural products from plants interact with these receptors, and the specific aim of phase 1 is to generate a """"""""natural product extract library"""""""" of compounds with these molecular actions using a plant genomics approach. The process is first to create a large population of plant microcultures in which """"""""gain of function"""""""" mutations have been produced. Each culture is a clone exhibiting the metabolic consequences of over-expression of one or more genes. An extract from each culture is then tested in high throughput pharmacological screens (HTPS) for interactions with NMDAR and/or nicAChR proteins in rodent brain membranes. """"""""Daughter"""""""" cultures that continue to produce extracts containing an """"""""excess"""""""" of receptor binding activity are regarded as positive, and these clones are the deliverables for phase 1. In phase 2, active extracts will be analyzed by GC/MS to identify those in which """"""""novel"""""""" active compounds may be present in excess. These extracts will be evaluated functionally, and then tested in cellular and animal models relevant to relapse. In phase 3, potential products will be commercialized with a partner specializing in pharmaceutical natural products.
| Lutz, Joseph A; Kulshrestha, Manish; Rogers, Dennis T et al. (2014) A nicotinic receptor-mediated anti-inflammatory effect of the flavonoid rhamnetin in BV2 microglia. Fitoterapia 98:11-21 |
