Acetylcholine mediates a variety of responses in the central nervous system and throughout the body via muscarinic receptors. Five subtypes of muscarinic receptors, belonging to the family of G-protein-coupled receptors, have been identified through molecular biological studies. Although much is known about the biochemical and physiological responses elicited or prevented by muscarinic receptor ligands, comparatively little is known regarding the interaction of agonists and antagonists with muscarinic receptor subtypes at the molecular level. Such information is vital for efforts to develop selective ligands for the treatment of neurological disorders such as Alzheimer's disease. The present proposal focuses on understanding the interaction of ligands with muscarinic receptor subtypes at the molecular level. Molecular modeling and computational chemical approaches will be used to develop models of muscarinic receptor subtypes for use in docking studies. Biochemical studies will examine the binding affinities and agonist activities of ligands at muscarinic receptor subtypes expressed in cell lines. Molecular biological approaches will be used to generate receptors with point mutations to examine further the interaction of ligands with key amino acid residues on muscarinic receptor subtypes. Chemical synthesis will focus on a few key compounds with the aim of exploring the molecular features important for ligand binding and activity. Quantitative structure activity studies will help identify the molecular features which contribute to ligand activity and provide a basis for the rational design and synthesis of new ligands. The overall goal of the proposed studies is to identify molecular features important for ligand affinity and agonist activity at muscarinic receptor subtypes. These studies will be helpful in generating new compounds with improved selectivity for muscarinic receptor subtypes, and aid in the development of novel ligands for the treatment of Alzheimer's disease and other neurological disorders.
