Fig 1.
Structures of PCP and related arylcyclohexylamines, ‘legal highs’ DPH, 2-MXP and aryl-substituted 1,2-diarylethylamines.
Table 1.
NMDAR binding affinities for five target 1,2-diphenylethylamines and reference compounds
Fig 2.
Heat map of receptor binding affinities observed for NMDAR and 45 additional receptor sites.
Ki values given in nM. Full green without numbers represents >10,000 nM in the primary screen.
Table 2.
Inhibition potencies of 1,2-diarylethylamines as monoamine transporter reuptake inhibitors.
Fig 3.
Comparison of effect of compounds on hippocampal fEPSPs.
A & B. Graphs showing basic method for studying effect of compounds on NMDAR-fEPSPs in CA1 region comparing effects of 10 μM D-AP5 (A) and DPH (B). After 30 min baseline recording (a), AMPA and GABA receptor mediated events were blocked pharmacologically (b), the stimulus strength increased and a new baseline was obtained for the NMDAR-fEPSP (c) before administering the test compound for 3 h (d). Note firstly the difference in shape between the AMPA receptor-mediated (a) and the NMDA receptor-mediated (c) fEPSPs, and secondly the slow onset of the pharmacological block by DPH (B) compared with D-AP5 (A). C. AMPA receptor-mediated fEPSPs (a) were not reduced by 50/100 μM 2-MXP (b) but the remaining NMDAR-fEPSPs after AMPA and GABA receptor antagonism were abolished in the presence of 10 μM 2-MXP(c). D. Superimposed single exponentials, showing time course of reduction of NMDAR-fEPSP by 1 μM test compounds superfused for up to 12 h.
Fig 4.
Graphs showing the time course of reduction of the NMDAR-fEPSPs by nine compounds.
Each graph shows the average fEPSP amplitude of 3–5 experiments expressed as a percentage of the amplitude during the prior baseline recording. Drugs were added to the aCSF at concentrations of either 1 μM (blue) or 10 μM (red). The figures on the graphs give i) the time to reach half the maximal response for each drug concentration and ii) the maximal effect; values derived from single exponential curve-fitting. In the case of memantine and 4-MXP only the 10 μM concentration was tested.
Fig 5.
Effects of (A) DPH and (B) 2-MXP on prepulse inhibition (PPI). (A1) Effect of DPH at doses ranging from 1.25–10 mg/kg. 50 rats were used (n = 10/group). (A2) Effect of DPH at doses ranging from 2.5–30 mg/kg. 49 rats were used (n = 9-10/group). (B1) Effect of 2-MXP at doses ranging from 1.25–10 mg/kg. 50 Rats were used (n = 10/group). (B2) Effect of 20 mg/kg 2-MXP. 24 rats were used (n = 12/group). PPI values shown are averaged across the 3 prepulse intensities (mean ± SEM). *Significant difference compared with vehicle control, p<0.01 (Tukey's test).