Synthesis and receptor‐affinity profile of N‐hydroxytryptamine derivatives for serotonin and tryptamine receptors. A molecular‐modeling study

The synthesis and the affinities for serotonin and tryptamine receptors of a series of N-oxy derivatives of tryptamine (6–8, 13–14) are reported. It was found that N-hydroxytryptamine (6) is a relatively selective ligand for the 5-HT1C receptor. The receptor-binding data are interpreted by a molecular modeling study in which the binding sites of the 5-HT1A and 5-HT1C receptors are compared. An asparagine residue present in helix 7 of 5-HT1A but absent in 5-HT1C plays a crucial role. On the basis of a three-dimensional model of the seven transmembrane regions of the 5-HT1A receptor a hydrogen-bond interaction is predicted between this asparagine residue and one of the oxygens of an aspartic acid residue on helix 3, leaving only one oxygen atom for ligand interaction. In the 5-HT1C both oxygens of the aspartic acid residue on helix 3 are free to interact via a doubly hydrogen-bonded complex with the N-hydroxy moiety of 6. N-Methoxy derivative 13 lacks this additional hydrogen-bond possibility and is devoid of binding affinity, presumably as a result of electrostatic repulsion.