Fig 1.
Chemical structure of the mGluR2 PAM JNJ42153605 (A) and in vitro pharmacological characterization thereof in vitro in CHO cells expressing the human and/or rat mGluR2 (B, C, D).
Fig 1B shows the [35S]GTPγS concentration-response curve of JNJ-42153605 in the absence or presence of an EC20 glutamate concentration. Data are expressed as percentage of the maximal response to glutamate and are mean ± S.E.M. of 9–10 experiments. Fig 1C represents glutamate-induced [35S]GTPγS binding in the absence or presence of increasing concentrations of JNJ-42153605. JNJ-42153605 shifts the glutamate concentration-response curve to the left in CHO cells expressing the human (left panel) or rat (right panel) mGluR2. Data for the human mGluR2 were repeated 3 times with similar results. Fig 1D shows [3H]LY341495 binding to the human mGluR2 in the presence of either LY404039 or JNJ-42153605. LY404039 but not JNJ-42153605 displaces [3H]LY341495 from the orthosteric agonist (glutamate) binding site.
Fig 2.
Close up view of the mGluR2 7TM binding site showing the proposed binding mode of JNJ-42153605.
Fig 3.
Percentage distribution of the vigilance states active wake, passive wake, intermediate stage, light sleep, deep sleep and rapid eye movement (REM) sleep for each hour period of the 20-h recording session following acute LY354740 (1, 3, 10 mg/kg) or vehicle.
Open and dark areas in the abscissa axis indicate light and dark phase of the circadian time, respectively. Values are presented as means ± S.E.M. for each condition expressed in percentage of the recording time. Each symbol indicates statistically significant difference (P < 0.05) between vehicle and drug-dose injected groups.
Fig 4.
Sleep parameters following repeated dosing with LY354740 (1, 3, 10 mg/kg) or vehicle on experimental days (D1 first treatment day till D7 seventh treatment day).
Total sleep time expressed in minutes (Panel A) and sleep efficiency expressed in percentage (Panel A inset). REM sleep amount during the first 4-h of recording sessions after repeated administration (Panel B) and REM sleep latency (Panel B inset). Total amount of REM sleep expressed in minutes that was recovered during the subsequent 10-h dark period (Panel C). The data are presented as means ± S.E.M. Significant differences between the vehicle and LY354740 group are indicated by the drug-dose symbol.
Fig 5.
Percentage distribution of the vigilance states active wake, passive wake, intermediate stage, light sleep, deep sleep and rapid eye movement (REM) sleep for each hour period of the 20-h recording session following acute JNJ-42153605 (3, 10, 30 mg/kg) or vehicle.
Open and dark areas in the abscissa axis indicate light and dark phase of the circadian time, respectively. Values are presented as means ± S.E.M. for each condition expressed in percentage of the recording time. Each symbol indicates statistically significant difference (P < 0.05) between vehicle and drug-dose injected groups.
Fig 6.
Sleep parameters following repeated dosing with JNJ-42153605 (3, 10, 30 mg/kg) or vehicle on experimental days (D1 first treatment day till D7 seventh treatment day), withdrawal days (W1 first withdrawal day till W3 third withdrawal day) and re-administration days after withdrawal (D’1 and D’2).
Total sleep time expressed in minutes (Panel A) and sleep efficiency expressed in percentage (Panel A upper inset). REM sleep amount during the first 4-h of recording session after repeated administration (Panel B) and REM sleep latency (Panel B upper inset). Total amount of REM sleep expressed in minutes that was recovered during the subsequent 10-h dark period (Panel C). The data are presented as means ± S.E.M. Significant differences between the vehicle and JNJ-42153605 group are indicated by the drug-dose symbol.
Table 1.
Summary of halve-lives (T1/2 expressed in h), brain receptor occupancy (Efficacy Dose “ED50” expressed in mg/kg) and pharmacodynamics effect of published mGluR2 PAMs (JNJ-40411813, JNJ-40068782, JNJ-42153605) on sleep measures in rats (Lowest Active Dose “LAD” expressed in mg/kg) [30,31,77].