Several 5-HT1D/1B receptor agonists are now entering the marketplace as tre
atments for migraine. This paper describes the development of selective h5-
HT1D receptor agonists as potential antimigraine agents which may produce f
ewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been
synthesized which has led tal the identification of 80 (L-772,405), a high
-affinity h5-HT1D receptor full agonist having 170-fold selectivity for h5-
HT1D receptors over h5-HT1B receptors. L-772,405 also shows very good selec
tivity over a range of other serotonin and nonserotonin receptors and has e
xcellent bioavailability following subcutaneous administration in rats. It
therefore constitutes a valuable tool to delineate the role of h5-HT1D rece
ptors in migraine. Molecular modeling and physical properties have been uti
lized to postulate the binding conformation of these compounds in the recep
tor cavity.