J. Macor, B. Chenard, R. Post
Dec 1, 1994
Citations
0
Influential Citations
26
Citations
Journal
Journal of Organic Chemistry
Abstract
During the course of our investigations2 into the use of conformationally restricted analogs of the neurotransmitter serotonin (5-HT, la [R1 = R2 = HI, Figure 1) as receptor probes, we became aware of the potential of the 3-(pyrrolidin-2(R)-ylmethyl) group in 2 as a replacement for the 3-(2-aminoethyl group) in 5-HT (Figure l).2g92h,2i33 This group was designed to be a stereogenic, metabolically stable, conformationally restricted replacement for the aminoethyl group of tryptamine^.^ Indoles containing the 3-(pyrrolidin-2(R)-ylmethyl) group (2) have generally been shown to have equal or improved serotonergic activity when compared to their corresponding tryptamine derivatives, especially at 5-HT1 receptor^.^ In fact, in a series of conformationally restricted analogs of the antimigraine drug sumatriptan (Imigran, lb [R1 = Rz = CH& the pyrrolidinylmethyl analog 2b was shown to have lo4 times greater potency in a measure of antimigraine activity when compared to sumatriptan (lb [RI = R2 = CH31) itselfU3 These results and others have led us to examine a number of 5-substituted-3-(pyrrolidinylmethy1)indoles for their activity at a variety of 5-HT receptors. Interest in 5-aminoindole analogs of serotonin has been ongoing since the initial discovery of the natural product in 1948. In both patent and primary literature, 5-aminoindoles have been cited as potentially important agents for the modulation of mammalian serotonergic function. Quite recently, we discovered a series of 5-[(3-nitropyrid2-yl)amino]indolesa which possessed varying degrees of serotonin receptor subtype selectivity. The most potent compound for the 5-HTm receptor subtype in this series was CP-135,807 [5-[(3-nitropyrid-2-yl)aminol-3-[(N-methylpyrrolidin-2(R)-yl)methyl]indolel which was directly derived from 5-amino-3-[(N-methylpyrrolidin-2(R)-yl)-