7. Project Summary/Abstract We aim to take advantage of traditional medicine knowledge to direct the discovery of novel therapeutics for mental disorders that will eventually help to unravel yet poorly understood biological processes behind the occurrence of mental disorders. Our previous studies have led us to collect information on the traditional use of plants for the treatment of mental disorders in several Peruvian localities and geographical regions. We have a repository of ethanol extracts from 477 plant collections corresponding to 265 species from 87 different plant families. These plants have been used for centuries in traditional medicine for one or more of the following activities: antipsychotic, antidepressant, anxiolytic and sedative. The overall long-term aim inherent to this proposal is to identify molecular pathways of neural function that are promising new intervention targets for mental disorders. For this specific R21 we aim to isolate of at least one novel neuroactive compound from plants used in Peruvian Traditional Medicine for the treatment of these disorders. The proposed work will have the support of the NIMH Psychoactive Drug Screening Program (PDSP) (a) to aid in the bioassays for the guided fractionation of the raw extracts we have in our repository and (b) to further consolidate an independent research platform for the study of novel drug targets for mental disorders based in our institution. Working in collaboration with the NIMH Psychoactive Drug Screening Program, we have been able to identify plant extracts from our repository which have potential agonist and inverse agonist activity for the orphan G-protein-coupled receptor (GPCR) GPR88 and potential agonist activity for the orphan GPCR MRGPRX4. Even when these two receptors belong to the rhodopsin (class A) family, which is the largest and extensively studied family of GPCRs, they are considered orphans because their endogenous ligands are yet unknown. Interestingly both receptors are expressed in the mammalian brain. An additional challenge is that there is a lack of pharmacologically active compounds identified or developed for these targets. GPCRs participate in diverse physiological functions and are promising targets for drug discovery. For this reason, the elucidation of their biological function is compelling. Our specific aims are: To isolate at least one novel active molecule through bioassay-guided fractionation (Tango assays) of the raw extracts that have shown either agonist or inverse agonist activity for orphan G-protein-coupled receptors (GPCR) GPR88 and MRGPRX4; To implement the needed bioassays (Tango assays) at the UPCH (acquisition of equipment, training of personnel), to be able to continue working independently in the future; To determine the molecular structure and dereplicate the isolated active compound(s); To evaluate the potential cytotoxicity, cardiotoxicity, and neurotoxicity of the isolated active compound(s); To train UPCH-located personnel in different aspects of genetically modified rodent models, to be prepared for the future steps in the discovery, i.e. managing tools for exploring the mechanisms of action and identifying molecular pathways of function.

8. Project Narrative Mental disorders are multidimensional, genetically complex and severely disabling diseases, with a strong need for pharmacotherapies with better adherence, long-term outcome and patient functionality. However, current advancements in the field have not yet led to the introduction of truly novel pharmacological approaches to treatment. We aim to take advantage of traditional medicine knowledge to direct the discovery of novel therapeutics for mental disorders that will eventually help to unravel yet poorly understood biological processes behind the occurrence of these diseases.