Computer-Aided Design and Synthesis of 5-Substituted Tryptamines and Their Pharmacology at the 5-HT1D Receptor: Discovery of Compounds with Potential Anti-Migraine Properties

Article abstract of DOI:10.1021/jm00018a016

The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT_1D and other monoamine receptors is described.Structural modifications of N- and C-linked (prinicipally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT_1D and 5-HT_2A receptor subtypes.Conformations of the active molecules were computed which, when overlaid, suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at 5-HT_1D and 5-HT_2A receptors.This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites.A 'selectively site' was also identified which, if occupied, induced selectivity for 5-HT_1D over 5-HT_2A in this series of molecules.The development and use of the pharmacophore models in compound design is described.In addition, the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed.Utilizing the pharmacophore model in conjuction with the physicochemical constraints of molecular size and log D_pH7.4 led to the discovery of 311C90 (6), a new selective 5-HT_1D agonist with good oral absorption and potential use in the treatment of migraine.