Synthetic combinatorial libraries [Nature, 354, 84-86 (1991)] have been used for the identification of new opioid ligands for the micro opioid receptor. The ligands identified have included peptides composed entirely of L- or D- amino acids, peptides composed of L- and D- amino acids and non-peptidic compounds (polyamines). Both agonists [Ac-rfwink-NH2, Science, 266, 2019-2022 (1994)] and antagonists [the acetalins, PNAS, 90, 10811-10815 (1993)] for the micro receptor have been identified using SCLs. Neither the acetalins nor the all D-amino acid peptide bear any obvious sequence relationship to the enkephalins or to other related opioid peptides. This study is currently being expanded to include the neurokinin receptors, initially the study will concentrate on neurokinin-1 receptors using a tritiated analogue of substance P (SP). In addition a receptor binding assay for methaqualone is currently being developed in this laboratory. The receptor to which this compound binds will be fully characterized using tritiated methaqualone. The radioreceptor assay for the neurokinin-1 receptor will be carried out using crude rat brain homogenates in Tris buffer (50mM Tris-HCl, 150mM NaCl, 5mM MnCl2, 0.1% BSA). Assays will be performed using an enzyme inhibitor cocktail which includes Leupeptin, Chymostatin and Bestatin. Each tube will contain 2-3 nM 3H-SP. The assay for methaqualone will use either rat brain or liver tissue. Conditions for this assay have yet to be determined. It is expected that new antagonists and agonists for the neurokinin-1 receptor will be identified as was found for the opioid receptors. New libraries are currently being synthesized which are expected to have greater stability and oral availability than peptides and thus will provide more useful new drug candidates. Initial experiments have demonstrated the presence of methaqualone binding sites in both liver and brain tissue. When fully characterized it is anticipated that use of combinatorial peptide libraries will enable the identification of a natural ligand for the methaqualone receptor.