# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 7 NR Derivatives and Supplementation  
During the state of physiological equilibrium, biosynthetic pathways rely on dietary sources of tryptophan (Trp), while NAD\({}^{+}\) precursor vitamins are compensating during periods of NAD\({}^{+}\) depletion. However, dietary precursors may become insufficient to maintain the NAD\({}^{+}\) levels in pathological conditions [14; 41; 169], thereby emphasizing the necessity of NAD\({}^{+}\) precursor supplementation. Besides the well-known vitamin B3 supplements (NA and NAM), NR and its phosphorylated form (NMN) have only recently become orally available as precursors of NAD\({}^{+}\)[11; 170; 171; 11]. On the other hand, the synthesis and manipulation of NR remain challenging, especially regarding its relatively labile glycosidic bond and the instability of NR salts [172]. However, great potential for the development of novel drugs and structural analogs of existing drugs can be achieved with the introduction of various chemical groups on the backbone of the molecule [172]. In general, there are two reported categories of synthetic pathway for nicotinamide riboside salts (NR\({}^{+}\)X\({}^{-}\)). Since only the \(\beta\)-form of NR\({}^{+}\) has biochemical and medical relevance, a valuable method of NR\({}^{+}\) synthesis should provide high levels of \(\beta\)-stereoselectivity. From two main synthetic pathways of NR, only one is predominately exploited and developed in terms of synthetic efficiency, stereoselectivity, and overall yield [172]. This method embodies the reaction between NAM or its analogs or derivatives and a peracylated (halo)-d-ribofuranose, resulting in the acylated intermediate that is subsequently converted into the desired NR\({}^{+}\)X\({}^{-}\)[173, 174]. The synthetic glycosylation conditions depend on the nature of the sugar component [172]. These conditions differ whether 1-halo-2,3,5- tri-o-acyl- or 1,2,3,5-tetra-O-acyl-d-ribofuranose is used since fully acylated ribofuranoses require the use of Friedel-Crafts catalysts that need to be activated as glycosylation reagents [172]. Furthermore, the X-ray structures of NR salts have already been determined. The NR derivatives nicotinamide-\(\beta\)-d-riboside chloride, nicotinamide-\(\beta\)-d-riboside bromide, thionicotinamide-\(\beta\)-d-riboside bromide, nicotinamide-\(\beta\)-d-riboside triacetate bromide, and thionicotinamide-\(\beta\)-d-riboside triacetate bromide were successfully crystallized by the vapor diffusion method [175]. Moreover, it was found that a crystalline form of nicotinamide ribose chloride has advantageous properties compared to amorphous forms, considering the possibilities for better purification [176]. However, further development of NR chemical synthesis along with a better understanding of the chemical versatility and reactivity of the ribosylated forms on the nicotinyl moiety would offer more reliable, more scalable, and more reproducible preparations of NR\({}^{+}\)X\({}^{-}\) salts [172]. In addition, effective modifications of the riboside residue of NR\({}^{+}\) at the 5\({}^{\prime}\)-hydroxy position could ensure higher yields, better recovery, and improved purification strategies [172]. This will enable the improved preparation of new pharmaceutically acceptable forms and potentially therapeutically useful forms of NR\({}^{+}\) in addition to the atom-efficient syntheses of isotopically labeled NR\({}^{+}\) analogs and derivatives [172]. Regarding a high demand for NR use in studies and for supplementation, new and reliable synthetic methods for NR production have been developed [177] during the past few years, enabling larger quantities available for cell-based studies and animal feeding experiments [37, 88]. NR has become available as a supplement in a form of crystalline chloride salt, in July 2013, with the brand name NIAGEN (Chromadex Inc., Irvine, CA, USA).