GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

A phase 1 randomized, placebo-controlled study to investigate potential interactions between ASP8062, a positive allosteric modulator of the GABAB receptor, and morphine in recreational opioid users.

BACKGROUND: Recent increases in opioid use and subsequent opioid use disorder are a major public health crisis in the United States. AIMS: This phase 1 randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics (PKs) of ASP8062, a γ-aminobutyric acid B receptor-positive allosteric modulator, with and without administration of morphine in participants who used opioids recreationally. METHODS: Participants were randomly assigned (2:1) to daily dosing with ASP8062 25 mg or placebo on days 1-10. On day 10, all participants received morphine as a single oral dose of 45 mg; assessments were performed on days 11-16. The primary end point was safety, evaluated as the nature, frequency, and severity of adverse events, and end-tidal CO2 levels. PK end points were a secondary outcome measure. RESULTS: A total of 24 participants (aged 21-54 years) received ASP8062 (n = 16) or placebo (n = 8). There were no deaths or serious adverse events leading to treatment discontinuation during the study. Most adverse events were mild, with numerically lower absolute number of adverse events reported with ASP8062 plus morphine versus placebo plus morphine. ASP8062 plus morphine did not increase respiratory depression, potential drug abuse- or withdrawal-related adverse events. There were no significant PK interactions. CONCLUSIONS: In this phase 1 study, we did not observe any unexpected safety signals or notable PK interactions with concomitant morphine administration. These data suggest a potentially low risk for an increase in drug abuse- or withdrawal-related adverse events or respiratory distress in participants exposed to ASP8062 and morphine.

A phase 1b study to investigate the potential interactions between ASP8062 and buprenorphine/naloxone in patients with opioid use disorder.

BACKGROUND: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD. AIMS: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®). METHODS: In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1-4; maintenance, Days 5-18; downward titration, Days 19-26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK. RESULTS: Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug-drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N. CONCLUSIONS: In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04447287.

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects.

BACKGROUND: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). AIMS: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. METHODS: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. RESULTS/OUTCOMES: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. CONCLUSION/INTERPRETATION: The data support further clinical studies investigating ASP8062 in patients with AUD.

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

INTRODUCTION/AIMS: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants. METHODS: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated. RESULTS: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (tmax ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367. DISCUSSION: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

Cortical influences of serotonin and glutamate on layer V pyramidal neurons.

Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT2A receptors. Serotonergic hallucinogens acting on 5-HT2A receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT2A receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT2A receptor activation and away from non-5-HT2A receptor activation. These 5-HT2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu2, mGlu4, and mGlu8 presynaptic receptors on thalamocortical terminals. These 5-HT2A receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator.

RATIONALE: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. OBJECTIVES: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). METHODS: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. RESULTS: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. CONCLUSIONS: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia. OBJECTIVE: The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies. METHODS: Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics. RESULTS: The plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain. CONCLUSIONS: The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia.

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Efficacy and Safety of ASP0819 in Patients with Fibromyalgia: Results of a Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects. PATIENTS AND METHODS: In this phase 2a, double-blind trial (NCT03056690), adults meeting fibromyalgia diagnostic criteria were randomized 1:1 to receive either 15 mg/day of oral ASP0819 (n=91) or placebo (n=95). The primary endpoint was the change from baseline to Week 8 in the mean daily average pain score. Changes in the Fibromyalgia Impact Questionnaire Revised (FIQR) symptoms, function, and overall impact subscales, as well as changes in the patients' global impression of change, were secondary endpoints; treatment effects on FIQR total score and impact on sleep were exploratory analyses. RESULTS: There was no statistically significant difference between ASP0819 and placebo for the primary endpoint (P=0.086); however, ASP0819 versus placebo significantly improved daily average pain at Weeks 2, 6, and 7 (all P<0.05). Numerical improvements were observed on the FIQR total score and several sleep items showed statistically significant improvements with ASP0819 versus placebo. There were no major safety concerns with ASP0819. Headache was the most common treatment-emergent adverse event (TEAE) occurring in both study arms; most TEAEs were mild or moderate in severity and no TEAEs suggestive of potential drug abuse were observed, as assessed by TEAE reporting and/or safety evaluations. Withdrawal effects also were not observed. CONCLUSION: ASP0819 demonstrated some signals suggestive of efficacy and had a good tolerability profile in patients with fibromyalgia. Further studies are required to determine if ASP0819 can be a novel non-opioid treatment option in this patient group. CLINICALTRIALSGOV REGISTRATION: NCT03056690.

Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats.

Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, double-blind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different metabotropic glutamate2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms, including differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior [increased reinforcers, decreased response rate, and cohesive rightward shifts in inter-response time distributions]. Although mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder, these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similarly to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive N-methyl-D-aspartate channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic versus antidepressant drugs and extend testing of compounds with glutamatergic mechanisms of action. SIGNIFICANCE STATEMENT: The metabotropic glutamate2/3 receptor agonist and clinically validated anxiolytic drug 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate did not test similar to antidepressant drugs (increased reinforcers, decreased response rate, and cohesive rightward shifts in the inter-response time distribution) when tested on differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior and also did not enhance the antidepressant-like effects of the serotonin reuptake inhibitor fluoxetine. The uncompetitive N-methyl-D-aspartate receptor antagonist ketamine increased the reinforcement rate, decreased the response rate, and induced a rightward shift in the inter-response time distribution similar to antidepressant drugs; these results confirm the utility of DRL 72-s schedule of reinforcement when testing clinically validated anxiolytic versus antidepressant glutamatergic drugs.

Single- and Multiple-Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies.

ASP8062 is an orally active γ-amino-butyric acid type B (GABAB ) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first-in-human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single-dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty-six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration-time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half-life were 1-4 hours and ∼40-50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2-fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

Imaging the Enzyme 11ß-Hydroxysteroid Dehydrogenase Type 1 with PET: Evaluation of the Novel Radiotracer 11C-AS2471907 in Human Brain.

The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11ß-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11ß-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer 11C-AS2471907 (3-(2-chlorophenyl)-4-(methyl-11C)-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4H-1,2,4-triazole) to image 11ß-HSD1 availability in the human brain with PET. Methods: Fifteen subjects were included in the study. All subjects underwent one 2-h scan after a bolus administration of 11C-AS2471907. Two subjects underwent an additional scan after blockade with the selective and high-affinity 11ß-HSD1 inhibitor ASP3662 to evaluate 11C-AS2471907 nondisplaceable distribution volume. Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of 11C-AS2471907 volumes of distribution (VT). Results:11C-AS2471907 time-activity curves were best fitted by the 2-tissue-compartment (2TC) model. 11C-AS2471907 exhibited a regionally varying pattern of uptake throughout the brain. The VT of 11C-AS2471907 ranged from 3.7 ± 1.5 mL/cm3 in the caudate nucleus to 14.5 ± 5.3 mL/cm3 in the occipital cortex, with intermediate values in the amygdala, white matter, cingulum, insula, frontal cortex, putamen, temporal and parietal cortices, cerebellum, and thalamus (from lowest to highest VT). From the blocking scans, nondisplaceable distribution volume was determined to be 0.16 ± 0.04 mL/cm3 for 11C-AS2471907. Thus, nearly all uptake was specific and the binding potential ranged from 22 in the caudate to 90 in the occipital cortex. Test-retest variability of 2TC VT values was less than 10% in most large cortical regions (14% in parietal cortex) and ranged from 14% (cerebellum) to 51% (amygdala) in other regions. The intraclass correlation coefficient of 2TC VT values ranged from 0.55 in the white matter to 0.98 in the cerebellum. Conclusion:11C-AS2471907 has a high fraction of specific binding in vivo in humans and reasonable within-day reproducibility of binding parameters.

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Inhibition of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11ß-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were observed for ASP3662 after single-dose administration, particularly at lower doses (≤ 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PKs were observed among young Japanese, young non-Japanese, and elderly non-Japanese subjects. Specific inhibition of 11ß-HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated.

Metabotropic Glutamate2 Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice.

There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A receptor activation using the mouse head twitch response (HTR). MGlu2 and mGlu3 receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity. DOI failed to produce significant head twitches in mGlu2 receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu3 receptor KO mice. In addition, the mGlu2/3 receptor agonist LY379268, and the mGlu2 receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu3 receptor KO mice. Conversely, the mGlu2/3 receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu3 receptor KO mice. Finally, the mGlu2 receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu3 receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu2 receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu2 receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu2 receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu2 receptor KO mice appears to reflect the critical role of glutamate in ongoing regulation of 5-HT2A receptors in the prefrontal cortex. Future experiments with inducible knockouts for the mGlu2 receptor and/or selective mGlu3 receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT2A receptor function.

ß2-Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate.

5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, µ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the ß2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 µM). Epinephrine (0.3-10 µM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective ß2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective ß2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3-3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective ß2-adrenergic receptor antagonist ICI-118,553 (0.01-1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, ß2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears to extend this suppressant action to a Gs-coupled GPCR. Furthermore, the modulation of 5-HT2A receptor activation-induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs.

Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons.

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or µ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

The impact of genetics on future drug discovery in schizophrenia.

INTRODUCTION: Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations. Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs. Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm.