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

The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT1D and other monoamine receptors is described. Structural modifications of N- and C-linked (principally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT1D and 5-HT2A 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-HT1D and 5-HT2A receptors. This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites. A "selectivity site" was also identified which, if occupied, induced sensitivity for 5-HT1D over 5-HT2A 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 conjunction with the physicochemical constraints of molecular size and log DpH7.4 led to the discovery of 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.