Investigational drugs for schizophrenia targeting the dopamine receptor: phase II trials

Introduction: For over half a century now, the dopamine hypothesis has provided the most widely accepted heuristic model linking pathophysiology and treatment in schizophrenia. Despite dopaminergic drugs being available for six decades, this system continues to represent a key target in schizophrenia drug discovery. The present article reviews the scientific rationale for dopaminergic medications historically and the shift in our thinking since, which is clearly reflected in the investigational drugs detailed. Areas covered: We searched for investigational drugs using the key words `dopamine,' `schizophrenia,' and `Phase II' in American and European clinical trial registers (clinicaltrials. gov; clinicaltrialsregister.eu), published articles using National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. We provide a brief description of drugs targeting dopamine synthesis, release or metabolism, and receptors (agonists/partial agonists/antagonists). Expert opinion: There are prominent shifts in how we presently conceptualize schizophrenia and its treatment. Current efforts are not as much focused on developing better antipsychotics but, instead, on treatments that can improve other symptom domains, in particular cognitive and negative. This new era in the pharmacotherapy of schizophrenia moves us away from the older `magic bullet' approach toward a strategy fostering polypharmacy and a more individualized approach shaped by the individual's specific symptom profile.

Effect of LHRH agonists and antagonists in male and female bonnet monkeys (Macaca Radiata)

A few analogues of LHRH have been tested in the adult bonnet monkeys using change in serum testosterone following LHRH injection as a parameter of response to LHRH. Of the four analogues tested in male monkeys, Buserelin was found to be the most potent one in increasing serum testosterone levels. Injection of the LHRH antagonist at 1600 h resulted in the abolition of the characteristic nocturnal surge of testosterone observed in adult bonnet monkeys maintained under regulated light conditions. Following administration of LHRH a/s during early pregnancy, serum chorionic gonadotropin levels decreased though the course of pregnancy was not affected. These results suggest that bonnet monkey can be successfully employed to test LHRH analogues.

Synthesis, X-ray structure and catalytic properties of a copper(II) Schiff base complex modeling the activity of the Cu-B site of dopamine beta-hydroxylase

The copper(II) complex [Cu(salgly) (bpy)] . 4H(2)O (1), where salgly is a tridentate glycinatosalicylaldimine Schiffbase Ligand, is prepared and structurally characterized. The complex is found to be catalytically active in the oxidation of ascorbic acid by dioxygen and the process is also effective in the presence of benzylamine giving benzaldehyde as a product, thus modeling the activity of the Cu-B site of dopamine beta-hydroxylase. (C) 2000 Elsevier Science S.A. All rights reserved.

Dopamine receptors in human foetal brains:Characterization, regulation and ontogeny of [3H]spiperone binding sites in striatum

Eighteen corpora striata from normal human foetal brains ranging in gestational age from 16 to 40 weeks and five from post natal brains ranging from 23 days to 42 years were analysed for the ontogeny of dopamine receptors using [3H]spiperone as the ligand and 10 mM dopamine hydrochloride was used in blanks. Spiperone binding sites were characterized in a 40-week-old foetal brain to be dopamine receptors by the following criteria: (1) It was localized in a crude mitochondrial pellet that included synaptosomes; (2) binding was saturable at 0.8 nM concentration; (3) dopaminergic antagonists spiperone, haloperidol, pimozide, trifluperazine and chlorpromazine competed for the binding with IC50 values in the range of 0.3–14 nM while agonists—apomorphine and dopamine gave IC50 values of 2.5 and 10 μM, respectively suggesting a D2 type receptor.Epinephrine and norepinephrine inhibited the binding much less efficiently while mianserin at 10 μM and serotonin at 1 mM concentration did not inhibit the binding. Bimolecular association and dissociation rate constants for the reversible binding were 5.7 × 108 M−1 min−1 and 5.0 × 10−2 min−1, respectively. Equilibrium dissociation constant was 87 pM and the KD obtained by saturation binding was 73 pM.During the foetal age 16 to 40 weeks, the receptor concentration remained in the range of 38–60 fmol/mg protein or 570–1080 fmol/g striatum but it increased two-fold postnatally reaching a maximum at 5 years Significantly, at lower foetal ages (16–24 weeks) the [3H]spiperone binding sites exhibited a heterogeneity with a high (KD, 13–85 pM) and a low (KD, 1.2–4.6 nM) affinity component, the former accounting for 13–24% of the total binding sites. This heterogeneity persisted even when sulpiride was used as a displacer. The number of high affinity sites increased from 16 weeks to 24 weeks and after 28 weeks of gestation, all the binding sites showed only a single high affinity.GTP decreased the agonist affinity as observed by dopamine competition of [3H]spiperone binding in 20-week-old foetal striata and at all subsequent ages. GTP increased IC50 values of dopamine 2 to 4.5 fold and Hill coefficients were also increased becoming closer to one suggesting that the dopamine receptor was susceptible to regulation from foetal life onwards.

Renewable surface electrodes based on dopamine functionalized exfoliated graphite: NADH oxidation and ethanol biosensing

Exfoliated graphite (EG) was modified by covalently attaching dopamine (DA) (3,4-dihydroxyphenethylamine) through amide linkages, using -COOH groups introduced on the EG surface. The modified material was characterized by FT-IR spectroscopy, Xray photoelectron spectroscopy and electrochemical techniques. Composites of DA modified EG dispersed in organically modified silicates were prepared by a sol-get process. Electrodes were fabricated by casting the composites in glass tubes. The sol-gel based electrodes were found to be active for the electrocatalytic oxidation of NADH and biosensing of ethanol in presence of NAD(+) and alcohol dehydrogenase enzyme. The modified composite electrodes were found to be stable for several months. The surface of the electrode could be renewed just by mechanically polishing the electrode using emery sheets. The modified EG was also pressed and restacked in the form of a pellet and the use of this material as a binderless bulk-modified electrode was also demonstrated. The performance of sol-gel derived composite EG electrodes with binderless bulk-modified EG electrodes was compared. (C) 2002 Elsevier Science B.V. All rights reserved.

Structural model for the Cu-B site of dopamine beta-hydroxylase: Crystal structure of a copper(II) complex showing N3OS coordination with an axial sulfur ligation

A copper(II) complex containing a NSO-donor Schiff base and NN-donor 2,2'-bipyridine has been prepared and structurally characterized. The square pyramidal complex with an axial sulfur ligation is a structural model for the CUB site of dopamine-hydroxylase in its oxidized form. The copper(II) complex is catalytically active in the oxidation of ascorbic acid by dioxygen mediated by a copper(I) species which is proposed to have a four-coordinate structure with a N3S coordination geometry.

Immunomodulation using agonists and antagonists: potential clinical applications

Introduction: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics. Areas covered: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1 beta receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials. Expert opinion: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic.

ZnO and ZnO/polyglycine modified carbon paste electrode for electrochemical investigation of dopamine

Present work describes the characterization of commercially available ZnO and its electrochemical investigation of dopamine in the presence of ascorbic acid. ZnO was characterized by powder XRD, UV-visible absorption, fluorescence, infrared spectroscopy and scanning electron microscopy. The carbon paste electrode was modified with ZnO and ZnO/polyglycine for further electrochemical investigation of dopamine. The modified electrode shows good electrocatalytic activity towards the detection of dopamine with a reduction in overpotential. The ZnO/polyglycine modified carbon paste electrode (CPE/ZnO/Pgl) shows excellent electrochemical enhancement of peak currents for both dopamine (DA) and ascorbic acid (AA) and for simultaneous detection of DA in the presence of high concentrations of AA with 0.214 V oxidation peak potential differences between them at pH 7.4. From the scan rate variation and concentration, the oxidation of DA and AA was found to be adsorption-controlled. The use of CPE/ZnO/Pgl is demonstrated for the detection of DA in blood serum and injection samples. This journal is © The Royal Society of Chemistry 2012.

Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials

Introduction: Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D-2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. Areas covered: A search was carried out for investigational drugs using the key words `dopamine', `schizophrenia' and `Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. Expert opinion: There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-a-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation.

Superior Performance of a MoS2-RGO Composite and a Borocarbonitride in the Electrochemical Detection of Dopamine, Uric Acid and Adenine

A MoS2-RGO composite and borocarbonitride (BC5N) have been used as electrodes to selectively detect dopamine and uric acid in the presence of ascorbic acid. Both the electrodes show excellent eletrocatalytic activity towards the detection of dopamine, the detection limits being 0.55 mu M and 2.1 mu M in the case of MoS2-RGO and BCN respectively. MoS2-RGO shows a linear range of current over the 1-110 mu M concentrations of dopamine, while BCN shows over the 2.3-20 mu M range. BCN also exhibits satisfactory performance in the oxidation of uric acid with a detection limit of 3.8 mu M and the linear range from 4 to 40 mu M. The MoS2-RGO has also been used to detect adenine as well.

Molecule Modeling of Human Pentameric alpha(7) Neuronal Nicotinic Acetylcholine Receptor and Its Interaction with its Agonist and Competitive Antagonist

The nicotinic Acetylcholine Receptor (nAChR) is the major class of neurotransmitter receptors that is involved in many neurodegenerative conditions such as schizophrenia, Alzheimer's and Parkinson's diseases. The N-terminal region or Ligand Binding Domain (LBD) of nAChR is located at pre- and post-synaptic nervous system, which mediates synaptic transmission. nAChR acts as the drug target for agonist and competitive antagonist molecules that modulate signal transmission at the nerve terminals. Based on Acetylcholine Binding Protein (AChBP) from Lymnea stagnalis as the structural template, the homology modeling approach was carried out to build three dimensional model of the N-terminal region of human alpha(7)nAChR. This theoretical model is an assembly of five alpha(7) subunits with 5 fold axis symmetry, constituting a channel, with the binding picket present at the interface region of the subunits. alpha-netlrotoxin is a potent nAChR competitive antagonist that readily blocks the channel resulting in paralysis. The molecular interaction of alpha-Bungarotoxin, a long chain alpha-neurotoxin from (Bungarus multicinctus) and human alpha(7)nAChR seas studied. Agonists such as acetylcholine, nicotine, which are used in it diverse array of biological activities, such as enhancements of cognitive performances, were also docked with the theoretical model of human alpha(7)nAChR. These docked complexes were analyzed further for identifying the crucial residues involved i interaction. These results provide the details of interaction of agonists and competitive antagonists with three dimensional model of the N-terminal region of human alpha(7)nAChR and thereby point to the design of novel lead compounds.

Redistribution of subcellular calcium in rat liver on administration of vanadate

Mitochondria isolated from the livers of rats administered with sodium meta-, ortho-, or polyvanadate, but not vanadyl sulphate, exhibited enhanced Ca2+ — stimulated respiration and uptake of calcium. These effects were shown also by mitochondria isolated from livers perfused with polyvanadate. The concentration of acid-soluble calcium decreased significantly in the mitochondrial fraction on vanadate treatment, while that in the cytosol showed a corresponding increase. Phenoxybenzamine, an antagonist to a-adrenergic receptors, effectively inhibited vanadate-induced Ca2+ mobilization, but surgical sympathectomy was without effect. This is the first demonstration of vanadate mimicking agr-adrenergic agonists in vivo.

Impaired conflict monitoring in Parkinson's disease patients during an oculomotor redirect task

Fallibility is inherent in human cognition and so a system that will monitor performance is indispensable. While behavioral evidence for such a system derives from the finding that subjects slow down after trials that are likely to produce errors, the neural and behavioral characterization that enables such control is incomplete. Here, we report a specific role for dopamine/basal ganglia in response conflict by accessing deficits in performance monitoring in patients with Parkinson's disease. To characterize such a deficit, we used a modification of the oculomotor countermanding task to show that slowing down of responses that generate robust response conflict, and not post-error per se, is deficient in Parkinson's disease patients. Poor performance adjustment could be either due to impaired ability to slow RT subsequent to conflicts or due to impaired response conflict recognition. If the latter hypothesis was true, then PD subjects should show evidence of impaired error detection/correction, which was found to be the case. These results make a strong case for impaired performance monitoring in Parkinson's patients.

Preparatively useful transformations of steroids and morphine alkaloids byMucor piriformis

A versatile fungus isolated in our laboratory and identified as Mucor piriformis has been shown to effect novel and preparatively useful transformations in steroids and morphine alkaloids. The organism very effectively carries out hydroxylation of various C-19 and C-21 steroids at 7 and 14-positions. Although the organism is capable of catalysing hydroxylation at 6 beta and 11 alpha-positions, these are not the major activities. The 14 alpha-hydroxylase appears to have a broad substrate specificity. However, steroids with a bulky substitution at C-17 alpha-position or without the 4-en-3-one group are not accepted as substrates by the 14 alpha-hydroxylase system. Studies have demonstrated how various C-19 and C-21 steroids can be modified to yield new structures which are either difficult to prepare by traditional methods or hitherto unknown. The organism also very efficiently and selectively carries out the N-dealkylation of thebaine and its N-variants. Interestingly, the nor-compound formed does not get further metabolized. Since thebaine is very often used as a starting material to synthesize various morphine agonists as well as antagonists, and one of the steps involved in their preparation is the N-dealkylation reaction, the microbial process could certainly offer an alternative approach.

The requirements for Ca2+, protein phosphorylation and concurrent protein synthesis for zeatin signaling of acidic chitinase transcript accumulation in Cucumis sativus L

We have previously reported that both Ca2+ and staurosporine-sensitive protein kinase(s) are involved in the cytokinin zeatin induction of cucumber chitinase activity and its protein content (Barwe et al. 2001). To further characterize signal transduction events involved in this cytokinin induction of chitinase gene expression, Northern hybridizations of total RNAs prepared from excised, dark-grown cucumber cotyledons treated with cytokinins and/or various agonists and antagonists of signal transduction components, were carried out using a cucumber acidic chitinase (CACHT) cDNA probe (Metraux et al. 1989). CACHT mRNA increased by approximately 5- to 6-fold in response to exogenous zeatin (Z), zeatin riboside (ZR), and benzyladenine (BA) treatment, but failed to accumulate in response to kinetin (K). Among the cytokinins tested, Z was most effective. The Z-induced accumulation of CACHT mRNA was inhibited by a plasma membrane Ca2+ channel blocker verapamil. Treatment of cotyledons with exogenous CaCl2 and calcium ionophore A23187 in the presence and absence of cytokinin enhanced CACHT mRNA accumulation. These two observations suggest the participation of extracellular calcium in signaling Z-induction. Furthermore, the presence of staurosporine (an inhibitor of protein kinase) in Z treatment reduced CACHT mRNA, suggesting the involvement of phosphorylation of one or more cellular proteins. In addition, we provide evidence that the Z-induction of CACHT mRNA is blocked by protein synthesis inhibitor cycloheximide treatment. Taken together, these results suggest that Ca2+ influx from extracellular space, protein phosphorylation, and concurrent protein synthesis events participate in cytokinin signaling during Z-induced CACHT transcript accumulation.