D-Lysergic acid diethylamide (LSD) and D-2-bromolysergic acid diethylamide (BOL) act as competitive antagonists of histamine-activated adenylate cyclase in broken cell preparations from guinea pig hippocampus and cortex. The adenylate cyclase is linked to the histamine H2-receptor. Both compounds show structural similarity to potent H2-antagonists. BOL is 10 times more potent as an H2-antagonist than cimetidine, the most potent H2-antagonist previously reported, while LSD is about equipotent to cimetidine. Blockade of H2-receptors may contribute to the behavioral effects of these compounds.
Indole agonists at the human serotonin 5-HT2A receptor achieve differing efficacies through specific hydrogen-bond interactions with serine residues in helices 3 and 5. Serotonin forms hydrogen bonds with Ser3.36 and Ser5.46; methyl-substitution of the cationic primary amine or the backbone N1-amine disrupts these bonds and reduces efficacy. Mutating Ser3.36 to alanine largely eliminates efficacy differences caused by cationic amine substitution, while mutating Ser5.46 to alanine reduces the efficacy loss from N1-amine substitution. Computational modeling shows these interactions shift the agonist's position in the binding pocket, and the indole ring's position correlates with agonist activity. The findings support a mechanism where agonist position, influenced by specific helix interactions, determines receptor activation, likely shared by other class A G-protein coupled receptors.
A mechanistic hypothesis explains how drugs are recognized by a serotonin (5-HT) receptor in the brain that also binds LSD. The hypothesis links a drug's affinity for this receptor to an intramolecular rearrangement that aligns the electrostatic orientation vector of its indole portion with that of serotonin itself. To test this, a new series of tryptamine derivatives with methylenedioxy substituents at the 5,6 or 4,5 positions was studied. Their reactivity characteristics and theoretical predictions for activity at the 5-HT/LSD receptor are presented, based on electrostatic potential comparisons and simulations of molecular interactions with an imidazolium cation probe. Preliminary experimental binding data for these derivatives confirm that affinity can be predicted by the hypothesis.