3-[3-(Piperidin-1-yl)propyl]indoles as Highly Selective h5-HT1D Receptor Agonists

Several 5-HT1D/1B receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT1D receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to 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 selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT1D receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.