MODERN DRUG DEVELOPMENT FROM TRADITIONAL MEDICINAL-PLANTS USING RADIOLIGAND RECEPTOR-BINDING ASSAYS

Traditional medicinal plants in various countries, particularly in Ind ia have been used for centuries for various ailments; however, there h as been little scientific effort to validate these anecdotal uses ment ioned in the literature. A number of these traditionally used plant ex tracts and various ''Ayurvedic medicines'' that are highly valued in A yurveda, the traditional system of medicine in India for antiaging, me mory-enhancing, nerve tonic, anxiolytic, anti-inflammatory and immunop otentiation, have been screened using National Institutes of Mental He alth (NIMH) Synthetic Screening Program for scientific validation and the development of new leads of psychotherapeutic compounds using Radi oligand Receptor Binding Assays (RRA). Crude methanolic extracts of pl ants are screened using approximately 40 different in vitro RRA (prima rily from rat brain homogenates) and 6 enzyme assays including acetylc holine esterase, choline acetyltransferase, and monoamine oxidase (MAO ), A and B. The total crude extracts of many of these plants showed po tent selectivity to various receptors, especially gamma-Amino Butyric Acid (GABA(A)), N-Methyl-D-Aspartic Acid (NMDA), and MAO receptors, wh ich are presumed to be involved in mental disorders. The focus was on plants showing the highest displacement of GABA, cholecystokinin (CCK) , NMDA, MAO, and benzodiazopines. Bioassay guided fractionation of the most active extracts resulted in pure compounds which retained the or iginal activity of the crude extract validating the folkloric use. A b ioactivity-guided fractionation of Terminalia bellerica fruit extract led to the isolation of several pure compounds which retained the orig inal activity of the crude extract for CCK and GABA receptors, with th e exception of compound B3EA-6, which exhibited high affinity for Neur okinin receptor (Substance K similar to NK-1). The absolute structure of B3EA-6 has been established by x-ray crystallography. (C) 1998 John Wiley & Sons, Inc.