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  • Based upon the present findings it

    2021-09-17

    Based upon the present findings, it is tempting to imagine that selective, and especially stable blood–brain barrier (BBB) penetrating GalR1 antagonists might be useful as drugs for acute suppression of appetite. While this may be possible, previous studies LDE225 Diphosphate using nonspecific galanin antagonists yielded inconsistent effects on baseline food consumption (Corwin et al., 1993, Crawley et al., 1993, Leibowitz and Kim, 1992). Another related issue to bear in mind is that the current experiments were conducted during the light phase. The dark phase is generally where food consumption is highest in rodents (Johnson and Johnson, 1990) and galanin gene expression and LDE225 Diphosphate tissue levels are highest during the middle of the dark phase (Akabayashi et al., 1994, Xu et al., 1999). While the present low endogenous galanin levels would seem to be ideal for testing exogenously applied agonists, high endogenous galanin levels associated with feeding might overwhelm pharmacological actions of exogenously applied ligands, limiting generality of the findings to naturalistic feeding situations. Nonetheless, there is a continuous need for systemically active and subtype specifically binding galanin ligands and there are only few systemically active galanin agonists such as galnon (Saar et al., 2002), galmic (Bartfai et al., 2004) and Gal-B2 and its analogues (Bulaj et al., 2008, Robertson et al., 2010), available as of yet. Galnon and galmic interact with a variety of G-protein-coupled receptors including 5-HT-1A, 1B receptors, D2 dopamine receptors, ghrelin and melanocortin receptors (Bulaj et al., 2008, Florén et al., 2005). For Gal-B2 and some of its analogues, preferred binding has been shown for GalR1 over GalR2. Unfortunately, the binding affinities of these compounds for GalR3 are not available, while none of these compounds have been tested on GalR3. In addition, there are no studies performed on the amounts of Gal-B2 and its analogues that can cross the BBB. The ability of the previously mentioned peptides to penetrate BBB has been shown only as biological effects in in vivo studies (Bulaj et al., 2008, Robertson et al., 2010). Modifications on M1153 to improve its ability to penetrate BBB and to make it metabolically more stable would lead to a powerful tool to study the involvement of GalR2 in vivo in different diseases and stages of diseases. There is however still a big obstacle to overcome, since even minor changes in the sequence of the peptide tend to decrease its binding properties and subtype specificity. In summary, the present findings show that M617 vs. M1153/M1145 used in combination may be a useful approach for looking at specific roles of galanin receptors in other functions (Mitsukawa et al., 2008). However, the development of additional antagonistic ligands for GalR2 as well as GalR3 selective ligands may reveal additional regulatory roles for these receptor subtypes in the long-term regulation of feeding behavior or in modulating the effects of GalR1 stimulation.
    Acknowledgments