One hundred years of histamine research.

In this introductory chapter, we revisit some of the landmarks in the history of histamine research. Since histamine was first synthesized (1907) and isolated as a bacterial contaminant of an extract of ergot (1910), the elucidation of its role in health and disease and its molecular mechanism of action have been continuous, reflecting the application of advances in scientific knowledge, technology and therapeutics over the last 100 years. It appears that the research will continue indefinitely as the nature of the problem is inherently fractal. First, there was a single chemical entity, described in terms of state-of-the-art, two-dimensional projections of structures introduced by Fischer in 1891, and an idea that such potent chemicals produced their effects on biological systems as a consequence of an exquisite interaction with a receptive substance, the revolutionary concept of Langley (1905). Today, we recognize four receptor subtypes with multiple activation states and multiple coupling to intracellular effector systems, so that we are no longer able to reliably and in all instances classify compounds interacting with the histamine receptors simply as agonists or antagonists. The complexity is potentially overwhelming, but the promise of value to patients beyond that already provided by the first approved generations of histamine receptor blockers is a compelling driver.