Isolation and identification of CXCR4 and CXCR7 agonists from traditional phytopharmaceuticals as potential novel drugs for mental disorders

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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 these diseases. Previous studies have led us to collect information on the use of plants for treating 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 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 novel neuroactive compounds acting on the chemokine G- protein coupled receptors (GPCRs) CXCR4 and CXCR7. 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 these specific novel drug targets, based in our institution. Working in collaboration with the PDSP we have been able to identify 58 extracts from our repository which showed potential agonist activity for CXCR4 and CXCR7 receptors in a primary functional screen. From them, 3 extracts show dose-dependent response curves for both CXCR4 and CXCR7, and 12 for CXCR7 alone. CXCR4 and CXCR7 act as receptors for the CXC chemokine ligand 12, CXCL12 (also called SDF-1 alpha). Evidence supports their role in the interaction between the nervous and immune systems. The involvement of CXCR4 and CXCR7 in mental disorders has started to be discussed only in the past few years. Our data, showing that botanicals used for treating mental disorders contain agonists for these receptors support this possible role. 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 perform bioassay-guided fractionation of the 15 extracts active at CXCR4 or CXCR7, to dereplicate and determine the molecular structure of the isolated active compound(s), and to provide outstanding students located in Peru the opportunity to do their thesis work, present their results at major international conferences, and to train on drug discovery research approaches.