Defining the histamine H2-receptor in brain: the interaction with LSD

Two aspects of the complexities of the mode of action of drugs are described. One is the criteria and pitfalls of defining the interaction with specific receptors. The other is the need to consider each of the pharmacological effects of a drug as a concatenation of receptor events, because it has become clear that each drug may have substantial affinity for many specific receptors. Illustrating these ideas is a characterization of the histamine receptor linked to adenylate cyclase in brain. The activities of a series of H2-antagonists and H2-agaonists were shown to be the same on the histamine receptor linked to adenylate cyclase as on known H2-receptors. The KB values of antagonists and ED50 values of agonists were not distinguishable among these receptors. Notably, at high concentrations, the H1-antagonists are also competitive antagonists of the H2-receptor. Cyproheptadine has especially high affinity for the H2-receptor. It is the most potent H2-antagonist yet reported. Other published results are reviewed to show the variety of receptors that cyproheptadine has affinity for. Its affinity for serotonin receptors led us to examine other serotonin antagonists. On this H2-receptor linked to adenylate cyclase in homogenates of guinea pig hippocampus and cortex, D-LSD and D-2-bromo-LSD (BrLSD) were shown to be competitive antagonists of histamine. L-LSD, mescaline and psilocin were inactive. Noting congurency in the molecular structyre of D-LSD and known H2-antagonists, we predicted a new H2-antagonist. This prediction is shown to be correct: the compound has similar affinity to the H2-receptor as has LSD. The affinities of D-LSD and BrLSD for the H2-receptor are compared with their affinities for other receptors. The pharmacology of D-LSD and BrLSD is reviewed. Evidence is assembled that BrLSD has considerable central effects.