Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor

The design, synthesis, and biological evaluation of a novel series of 3-[2- (pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (form erly 5-HT1D alpha) receptors over h5-HT1B (formerly 5-HT1D beta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors, The differen tial expression of h5-HT1D and h5-HT1B receptors in neural and vascular tis sue prompted an investigation of whether a compound selective for the h5-HT 1D subtype would have the same clinical efficacy but with reduced side effe cts. The pyrrolidine 3b was initially identified as having g-fold selectivi ty for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinon es 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improv ed selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [S-35]GTP gamma S bindin g in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substit ution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is abse nt for the h5-HT1B receptor. The compounds described herein will be importa nt tools to delineate the role of h5-HT1D receptors in migraine.