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

1999; American Chemical Society; Volume: 42; Issue: 24 Linguagem: Inglês

10.1021/jm9910021

1520-4804

Michael G. N. Russell, Victor G. Matassa, Roy R. Pengilley, Monique B. van Niel, Bindi Sohal, Alan P. Watt, Laure Hitzel, Margaret S. Beer, Josephine A. Stanton, Howard B. Broughton, José L. Castro,

Olfactory and Sensory Function Studies

Several 5-HT(1D/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D) 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-HT(1D) receptor full agonist having 170-fold selectivity for h5-HT(1D) receptors over h5-HT(1B) 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-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.