This is a proposal to develop new tools for the practical effective synthesis of N,N,O- trisubstituted hydroxylamines, or hydroxalogs, as novel isosteres for application in medicinal chemistry across a broad swath of compound classes and diseases states. The three specific aims presented encompass i) tools development for the synthesis of N,N,O-trisubstituted hydroxylamines by a variety of inter- and intramolecular methods; ii) synthesis of a series of phenylpropylpiperidine ligands for the σ-1 and σ-2 receptors and their use as models for the comparative study of the physical and drug-like properties of the hydroxalogs, thereby enhancing their applicability as tools in medicinal chemistry; iii) synthesis of a series of hydroxalogs of the ethanolamine H1 antagonists and comparative determination of their antihistamine activity in a cell-based assay, again with the view to validating the hydroxalogs as isosteres as tools in medicinal chemistry.