Fig. 4: Adenosine-based screening identifies ketamine analogues with potent antidepressant-like effects.
From: Adenosine signalling drives antidepressant actions of ketamine and ECT
a, Left, schematic of the ketamine analogue synthesis strategy. Right, scatter plot of peak adenosine amplitude compared with the AUC from an in vivo screen of synthesized compounds (10 mg kg−1, i.p. injection), normalized to ketamine responses. b, Time course of extracellular adenosine levels in the mPFC after administration of DCK (n = 7 mice), 2C-DCK (n = 8 mice), 3′-Cl-ketamine (n = 6 mice) or ketamine (n = 13 mice; 10 mg kg–1, i.p. injection; arrow). c,d, Comparison of peak adenosine levels (c) and AUC (d; normalized to saline) for DCK versus ketamine at an equivalent dose. e–g, Dose–response of DCK on adenosine release in the mPFC. e, Time course following injections of DCK (2, 5 and 10 mg kg−1, i.p. injection) or saline. f, Peak adenosine levels. g, AUC, normalized to saline. h,i, Rapid antidepressant-like effects of lead analogues. Immobility time in FSTs (h) and sucrose preference in SPTs (i) were measured in mice subjected to CRS 1 h after i.p. administration of ketamine, DCK, 2C-DCK or 3′-Cl-ketamine (3′-Cl-K). Data are the mean ± s.e.m. (shading in b and e; error bars in c, d and f–i). Box plots (c,d) show the median (centre line), first and third quartiles (box bounds), and 1.5× the interquartile range (whiskers). Statistics: two-tailed unpaired t-tests (c,d,f–i). *P < 0.05, **P < 0.01, ***P < 0.001. In h, significance is relative to the saline control. See Supplementary Table 1 for detailed statistics.
