Molecular determinants for binding of methylenedioxytryptamines at 5-HT/LSD 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.

Study at a glance

Abstract

In investigations of the molecular determinants for the recognition of drugs by a serotonin (5-HT) receptor in the brain, the commonality in the reactivity patterns of 5-HT congeners has been identified. On this basis a mechanistic hypothesis is proposed to explain the rank order of the affinity of drugs that bind to the receptor shared by 5-HT and LSD (the 5-HT/LSD receptor). This hypothesis describes the relation between affinity and the intramolecular rearrangement needed to make a 5-HT congener recognizable at the 5-HT/LSD receptor. The rearrangement of the congener aligns the electrostatic orientation vector of its indole portion in the direction defined by the vector in 5-HT. To further probe this mechanistic hypothesis the molecular determinants for the action of a new series of tryptamine derivatives was studied in which a methylenedioxy substituent is placed at the 5.6 or the 4,5 positions. The reactivity characteristics of these molecules are presented. The-oretical predictions for their activity on the 5-HT/LSD receptor are discussed. These predictions are based on the comparison of the electrostatic potentials of these molecules with the requirements for 5-HT-like recognition by the 5-HT/LSD receptor, and on simulations of molecular interactions with a molecular probe (imidazolium cztion) which represents a matching receptor site. The electrostatic nature of the complexes that these molecules form with imidazolium cation is revealed by the decomposition of the stabilization energy. It is shown that the affinity of these new compounds for 5-HT/LSD receptors can be predicted and explained on the basis of the working hypothesis obtained previously. Preliminary experimental data on the binding of 5,6- and 4.5-methylenedioxy derivatives of typtamine to the 5-HT/LSD receptors in brain confirm these findings.