Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Na1.7 for the Treatment of Pain.

Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels . The article describes the design of analogues of ProTx-II that safely display systemic blocking of Na1.7, resulting in a latency of response to thermal stimuli in rodents.

MitoPark mice, an animal model of Parkinson's disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A(2A) antagonist SCH 412348.

Rationale: Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis.

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625.

Rationale: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.

Objectives: We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.

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.

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes.

Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A(-/-) knockout (KO) mice.

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.

Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia.

Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats.

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.

Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders.

The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.

WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics.

Introduction: 5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics).

Objectives: The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur.

Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide).

The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in Alzheimer's disease and schizophrenia, leading to efforts targeted toward discovering agonists and positive allosteric modulators (PAMs) of this receptor. In a Ca2+ flux fluorometric imaging plate reader assay, SB-206553 (3,5-dihydro-5-methyl -N-3-pyridinylbenzo [1, 2-b:4,5 -b']-di pyrrole-1(2H)-carboxamide), a compound known as a 5-hydroxytryptamine(2B/2C) receptor antagonist, produced an 8-fold potentiation of the evoked calcium signal in the presence of an EC(20) concentration of nicotine and a corresponding EC(50) of 1.5 muM for potentiation of EC(20) nicotine responses in GH4C1 cells expressing the alpha7 receptor.

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity.

Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.