Peptides pharmaceutical significance

The Maillard reaction is likely to take on additional significance with the introduction of many new protein and peptide pharmaceuticals. For example, Tarelli et al. have demonstrated that lysine vasopressin undergoes rapid glycation in the presence of reducing sugars in both aqueous and solid formulations and that the N-terminal adduct can form rapidly even at — 20°C [52], A textbook that deals with the consequences for the chemical and life sciences of the Maillard reaction has been published [53]. 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

Polar organic compounds such as amino acids normally do not polymerize in water because of dipole-dipole interactions. However, polymerization of amino acids to peptides may occur on clay surfaces. For example, Degens and Metheja51 found kaolinite to serve as a catalyst for the polymerization of amino acids to peptides. In natural systems, Cu2+ is not very likely to exist in significant concentrations. However, Fe3+ may be present in the deep-well environment in sufficient amounts to enhance the adsorption of phenol, benzene, and related aromatics. Wastes from resinmanufacturing facilities, food-processing plants, pharmaceutical plants, and other types of chemical plants occasionally contain resin-like materials that may polymerize to form solids at deep-well-injection pressures and temperatures. 

The primary purpose of this chapter is to review the structure-activity relationships (SAR) of non-peptide kappa opioid agonists and antagonists from the viewpoint of a medicinal chemist. It is intended to present an account of work in this area published in journals and in patents from 1985 up to the end of 1990. During the late 1980 s there was a significant increase in the literature on kappa opioids and this has resulted in several publications which, at the time of writing, have not been previously reviewed. Three pharmaceutical companies, Upjohn, Parke-Davis and Zambeletti (SB-Italy), have progressed kappa agonists into clinical trials, so it seems an appropriate and opportune time to review the preclinical data. 

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