DESCRIPTION: (Verbatim from the Applicant's Abstract) We propose to identify high-affinity and subtype selective neuronal nicotinic acetylcholine receptor alpha7 ligands from alpha-conopeptide libraries. Such compounds represent novel therapeutic leads to treat Alzheimer's Disiease (AD). Emerging experimental data suggests the interaction of AD causative agen Amyloid beta-peptide with alpha7 receptors could be responsible for the pathological features of AD. Selective blockage of Abeta/alpha7 complex formation with alpha7 ligands is an attractive therapeutic stragegey. Alpha-conopepide ImI isd the most selecgive alpha7 ligand currently available. However, its affinity for human alpha7 receptors can still be improved. Since alpha-conopeptides targe a wide range of nNChRs, and since suble modivication of nAChR ligand can confer drastic change of affinity and selectivity for these ligans, synthesis and screeing of alph-conopeptide libraries could result in the identification human alpha7 ligands with higher affinity. In Phase I we will construct and screen libraries of alpha-conopeptides. In addtion, we will also use the structure-activity relationship data available for ImI to construct libraries with annatural amino acid building blocks. We expect to identify ImI derivatieves with improved affinity and stability from screen ing thesed libraries. In Phase II, we will carry out functional assays on the leads and proceed to subsequent rational drug design researchers. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE