Seite - (000316) - in Biomedical Chemistry: Current Trends and Developments

SP1–7-NH2 (15) and also 26 have been further tested regarding their potential antinociceptive effect in both non-diabetic and diabetic mice after intrathecal administration (Fig. 3.3.10) (Carlsson, 2010; Fransson, 2010b; Nyberg, 2010; Ohsawa, 2010; 2011). The use of diabetic mice for evaluation is due to their reduced pain threshold compared to non- diabetic mice, a reduction thought to arise from hyperalgesia caused by neuropathy, which makes them a good model for studying neuropathic pain. Interestingly, morphine was unable to induce any antinociceptive effect in the diabetic mice, whereas SP1–7 showed a dose-dependent antinociceptive effect in both diabetic and non-diabetic mice (Carlsson, 2010). The effect was higher in diabetic mice, which suggests that the compound is more effective on neuropathic pain and that SP1–7 ameliorates signs of hyperalgesia (Fig. 3.3.10). In agreement with the results obtained from the opioid withdrawal test, SP1–7-NH2 proved to be more efficient in reducing pain as compared to the native heptapeptide. It was also demonstrated that the dipeptide 26, which possessed the same binding affinity as SP1–7 (1), showed greater antinociceptive potency in diabetic mice than SP1–7 (Fransson, 2010b; Nyberg, 2010; Ohsawa, 2010). Figure 3.3.10: The antinociceptive effect of SP1–7 (1), SP1–7-NH2 (15) and H-Phe-Phe-NH2 (26) in non-diabetic (left) and diabetic (right) mice. The antinociceptive effect was evaluated by the AUC calculated from the time-response curve of tail-flick latency. Each column represents the mean with S.E.M. (n = 6). 3.3.2.3 Design and Synthesis of Small Constrained H-Phe-Phe-NH2 Analogs