Theoretical and experimental studies of drug-receptor interactions: Determinants for recognition of 5-hydroxytryptamine analogs

Abstract

Experimental studies on 5-hydroxytryptamine (5-HT) and its congeners have shown these compounds to interact with the same receptors in peripheral tissues and in brain. To evaluate the importance of the relative position of the 5-HT-like recognition elements at these receptors, we studied two compounds structurally related to 5-HT in which the structural elements involved in receptor recognition are positioned differently from 5-HT: 5-hydroxyaminotetrahydrobenzindole (FHATHBIN) in which the position of the side chain is fixed with respect to the indole, and 4(β-aminoethyl)-5-hydroxyindole (FAEFHI) in which the side chain is flexible, and connected to the indole at the C4 position (rather than at C3 as in 5-HT). Ab initio molecular orbital calculations of the molecules and model fragments were performed with STO-3G and 3-21G basis sets, using structural optimization procedures. The results show that both structures possess the reactivity elements required for the interaction with the 5-HT receptor, but that FAEFHI cannot be recognized at the 5-HT receptor because the side chain is held in the wrong conformation with respect to the indole portion by a strong hydrogen bond between the side chain amine group and the hydroxyl at C5. We report results from competition experiments for binding at high affinity 5-HT binding sites in brain membranes which support this conclusion by showing that FAEFHI has low affinity for these sites.