COMPUTER-AIDED-DESIGN AND SYNTHESIS OF 5-SUBSTITUTED TRYPTAMINES AND THEIR PHARMACOLOGY AT THE 5-HT1D RECEPTOR - DISCOVERY OF COMPOUNDS WITH POTENTIAL ANTIMIGRAINE PROPERTIES

The design and synthesis of a series of novel 5-substituted tryptamine s with pharmacological activity at 5-HT1D and other monoamine receptor s is described. Structural modifications of N- and C-linked (principal ly hydantoin) analogues at the 5-position were synthesized and their p harmacological activities were utilized to deduce significant steric a nd electrostatic requirements of the 5-HT1D and 5-HT2A receptor subtyp es. Conformations of the active molecules were computed which, when ov erlaid, 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 aromati c site, a hydrophobic pocket, and two hydrogen-bonding sites. A ''sele ctivity site'' was also identified which, if occupied, induced selecti vity for 5-HT1D over 5-HT2A in this series of molecules. The developme nt and use of the pharmacophore models in compound design is described . In addition, the physicochemical constraints of molecular size and h ydrophobicity required for efficient oral absorption are discussed. Ut ilizing the pharmacophore model in conjunction with the physicochemica l constraints of molecular size and log D-pH7.4 led to the discovery o f 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.