The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma.

Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.

Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia.

Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia.

A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia.

UNLABELLED: Vabicaserin, a potent 5-HT2C receptor agonist, decreases nucleus accumbens extracellular dopamine levels in rats, without affecting striatal dopamine, indicating mesolimbic selectivity. This is the first study of efficacy, safety and tolerability of vabicaserin in adults with acute schizophrenia. Three hundred fourteen hospitalized subjects were randomized to: Vabicaserin 200 or 400 mg/day, olanzapine 15 mg/day or placebo. Central raters assessed the PANSS and CGI-S. Site raters performed the BPRS and CGI-I. Central rated PANSS Positive (PANSS-PPS) was the primary endpoint. Two hundred eighty-nine subjects were included in the mITT efficacy analysis. Vabicaserin was well tolerated with no major safety concerns. Olanzapine, but not vabicaserin, caused weight gain. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement at week 6 vs. placebo on PANSS-PSS. A non-significant decrease vs. placebo was observed for 400 mg/day. Both vabicaserin groups demonstrated significant improvement over baseline on PANSS Negative while placebo worsened. Vabicaserin 200 mg/day and olanzapine demonstrated significantly greater improvement over placebo on PANSS Total whereas 400 mg/day showed a trend toward improvement. There was no significant improvement vs. placebo for either vabicaserin group on site-rated BPRS. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement vs. placebo on CGI-I and CGI-S but not 400 mg/day vabicaserin. Vabicaserin demonstrated efficacy on primary and secondary endpoints at 200 mg/day, but not at 400 mg/day which showed a trend for efficacy. The 200 mg/day vabicaserin group achieved proof of concept using central ratings. Both vabicaserin doses were well tolerated with no significant safety signals and no weight gain. TRIAL REGISTRATION: clinicaltrials.gov. Identifier: NCT00265551.

Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.

Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment.

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) α5 receptors might be useful in targeting this condition because GABA(A) α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABA(A) α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 µg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

5-HT(2C) agonists as therapeutics for the treatment of schizophrenia.

The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.

Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues.

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.

The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise?

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist.

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.

3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies.

A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).

Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo.

RATIONALE: The extended ternary complex theory of receptor function states a ligand can be classified as an inverse agonist, agonist, or neutral antagonist based on its ability to preferentially stabilize the inactive conformation, the active conformation, or to have no preference for conformational state, respectively. OBJECTIVES: While serotonin(2C) (5-HT(2C)) receptor ligands are classified accordingly in vitro, whether the phenomenon of inverse agonism manifests itself and/or is physiologically relevant in vivo is unknown. METHODS: Therefore, we tested a range of proposed agonists, neutral antagonists, and inverse agonists with activity at 5-HT(2C) receptors in three groups of pigeons trained to discriminate saline from: 1.0 mg/kg MK212, an agonist; 0.1 mg/kg methysergide, a proposed neutral antagonist; or, 10 mg/kg mianserin, a proposed inverse agonist. RESULTS: Based on the patterns of substitution, the discriminative stimulus effects of MK212 appear to be mediated through agonist actions and the stimulus effects of methysergide and mianserin appear to be mediated through antagonist actions. Selective 5-HT(2B/2C) inverse agonist SB206,553 (1 mg/kg) blocked the MK212 discriminative stimulus cue and substituted (0.32-10 mg/kg) in both methysergide- and mianserin-trained pigeons, confirming a 5-HT(2C) receptor role in mediating these discriminative stimuli. Inverse agonists and neutral antagonists fully substituted for methysergide. In addition to SB206,553, methysergide (0.032-1.0 mg/kg) and 5-HT(1A) agonist 8-OH-DPAT (0.32-1.0 mg/kg) substituted completely for mianserin suggesting a complex discriminative stimulus profile for this proposed inverse agonist. CONCLUSIONS: These data and the subsequent analyses suggest that the discriminative cues of MK212, methysergide, and mianserin are different and that the drug discrimination paradigm is a useful functional assay to examine intrinsic efficacy in vivo.

The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists.

As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.

Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation.

INTRODUCTION: The effects of angiotensin (Ang) IV result from binding to a constitutively active metallopeptidase known as the AT(4) receptor (or oxytocinase/insulin-regulated membrane aminopeptidase). While in vitro evidence indicates that Ang IV inhibits the peptidase activity of AT(4) receptors, leading to increases in the concentrations of several peptides, including oxytocin, the consequence of inhibiting AT(4) peptidase activity in vivo remains unresolved. DISCUSSION: Microdialysis coupled to immunoassay techniques revealed that systemic and intra-amygdala injection of Nle-Ang IV, a metabolically stable derivative of Ang IV, significantly elevated extracellular levels of oxytocin in the rat amygdala. Based on earlier reports describing the anxiolytic-like effects of oxytocin, we investigated whether disrupting AT(4) peptidase activity would yield similar responses. In the mouse four-plate test, acute treatment with either Nle-Ang IV or LVV-hemorphin-7, a related AT(4) receptor ligand, elicited significant increases in the number of punished crossings. These behavioral responses were comparable to the anxiolytic-like effects of oxytocin and to the standard anxiolytic agent, chlordiazepoxide. Cotreatment with either the AT(4) receptor antagonist, divalinal, or the selective oxytocin receptor antagonist, WAY-162720, reversed the anxiolytic-like effects of Nle-Ang IV, while combining ineffective doses of Nle-Ang IV and oxytocin increased the number of punished crossings in this assay. Conversely, Nle-Ang IV and LVV-hemorphin-7 were inactive in the mouse tail suspension test of antidepressant activity. These findings represent the first in vivo demonstration of the peptidase activity of AT(4) receptors, confirm the anxiolytic-like properties of Ang IV, and reveal a unique and previously uncharacterized relationship between AT(4) and oxytocin receptor systems.

Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity.

The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.

Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist.

The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.

The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?

In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.

Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT(6) agonists.

A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.