The large family of serotonin (5-HT) receptors provides a plethora of medicinally important targets, and the neurotransmitter serotonin has been implicated in a wide variety of disease states ranging from depression and anxiety to migraine and sexual dysfunction. The search for agents which can selectivity mimic or oppose the action of serotonin at a single receptor subtype, while leaving other 5-HT receptors unmolested, has become increasingly enticing with the almost continual discovery of novel receptor subtypes within the 5-HT family of receptors. There has already been success in this approach. Buspirone is a selective partial agonist at somatodendritic 5-HT1A autoreceptors, and this drug has been shown to be effective as an anxiolytic for generalized anxiety disorders. Even more recently, sumatriptan (Imigran), a 5-HT1-like agonist has been approved as a novel treatment for migraine headaches, and its selectivity for the 5-HT1D receptor has been proposed as the source of its antimigraine activity. The success of sumatriptan has initiated the search for other 5-HT1D receptor selective agonists with the purpose of further elucidating the mechanism of action of these compounds in relation to their antimigraine activity. During the course of our studies in the area of conformationally restricted agonists of serotonin, we became aware of the preference of the 5-HT1D receptor for the presence of a C5-hydroxy versus a C5-alkoxy substituent. Our efforts to optimize this preference led us to synthesize analogs with novel hydrogen bond donors located at C5 of the indole nucleus. Furthermore, our studies and the studies of others suggested the presence of a binding site within the 5-HT1D receptor which favored aromatic and heteroaromatic substitution proximate to C5 of the indole nucleus. This line of reasoning led to the replacement of C5-OH in serotonin with a C5-[(3-nitropyridyl)amino] substituent which we found to impart reasonable selectivity to the tryptamine derivative (10, Table 1). In this paper we present a novel series of 5-[(3-nitropyrid-2-yl)amino]indoles (5,8, 10, and 15) which have different types of conformational restraint of the C3-aminoethyl functionality. The binding and functional selectivity varies within this series of 5-HT1D agonists depending on the method of conformational constraint employed at C3 of the indole nucleus.