Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and secondgeneration antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits. Cognitive deficits were assessed using a frontally mediated attentional set-shifting task in rats that is analogous to tasks used in humans and nonhuman primates that assess executive function. Mirroring findings in patients with schizophrenia, the classical antipsychotic haloperidol was ineffective in treating set-shifting deficits induced by subchronic treatment with phencyclidine (PCP). Similarly, second-generation antipsychotics, risperidone, clozapine, and olanzapine were ineffective. In contrast, selected doses of sertindole and the 5-HT 6 receptor antagonist SB 271046 attenuated PCPinduced set-shifting deficits. Finally, the 5-HT 2A receptor antagonist M100907 was without effect. Further examination revealed that repeated treatment (21 days) with sertindole, but not olanzapine, also was effective in reversing the executive function deficit. These data suggest that the combination of 5-HT 6 antagonistic activity and the absence of antimuscarinic activity may represent key characteristics of the pharmacological profile for improved antipsychotic drugs for schizophrenia.

This study investigates the potential of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) to improve the bioavailability of poorly water-soluble drugs compared to conventional SNEDDS. Conventional SNEDDS contained simvastatin (SIM) at 75% of the equilibrium solubility (S (eq)). Super-SNEDDS containing SIM at 150 and 200% of S (eq) were produced by subjecting the SNEDDS preconcentrates to a heating and cooling cycle. The super-SNEDDS were physically stable over 10 months. During in vitro lipolysis of SNEDDS and super-SNEDDS the SIM concentration in the aqueous phase increased for the first 30 min almost proportional to the drug loads and amounts of preconcentrate employed. The 200% drug-loaded super-SNEDDS generated an amorphous SIM precipitate at the end of in vitro lipolysis. In vivo, the relative bioavailability of SIM from super-SEDDDS increased significantly to 180 ± 53.3% (p = 0.014) compared to the dosing of two capsules of (dose equivalent) 75% drug-loaded SNEDDS. A significant increase in the terminal half-life of elimination was observed for super-SNEDDS (2.3 ± 0.6 h) compared to conventional SNEDDS (1.4 ± 0.3 h) as well as a decreased area under the curve ratio of the SIM metabolite simvastatin acid to the parent compound (0.57 ± 0.20 and 0.90 ± 0.3), possibly due to a combination of saturation effects on presystemic metabolising enzymes and prolonged absorption along the small intestine. In summary, this study demonstrated that super-SNEDDS are a viable formulation option to enhance the bioavailability of poorly water-soluble drugs such as simvastatin while reducing the pill burden by an increased drug load of SNEDDS.

GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Å(2) and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.

Cytochrome c4 is a 190-residue protein active in the aerobic and anaerobic respiration of several bacteria. We have isolated Pseudomonas stutzeri (ATCC no. 11607) cytochrome c, by an optimized growth procedure following factorial design. The ultravioletlvisible spectra of reduced cytochrome c4 have a composite alp band which can be resolved into six components. One of these seems to be specific for the high-potential heme group. The kinetics for full oxidation and reduction with the two inorganic redox couples, [C~(terpy)~]*+'~+ and [C~(bipy),]~'/~+, is formally compatible with either bi-or tri-exponential kinetics. The former would be in line with weak interaction between the heme groups, the latter with notable interaction effects. Arguments in favour of the latter and a cooperative two-electron transfer pattern are given. All phases are approximately proportional to the Co-complex concentration, implying that intramolecular electron transfer in this time range is unlikely. The rate constants are in the range (0.7-80)X104 M-' s-' at pH = 7.6 (Tris) and 0.1 M NaCl and very little dependent on the ionic strength in the range 0.1-0.3 M. The reduction potentials could be calculated from the forward and reverse rate constant ratios. The values are 241 ? 5 and 328 -f 2 mV (Nernst hydrogen electrode) if bi-exponential kinetics is used and interaction between the heme groups disregarded. The intrinsic microscopic reduction potential values are closer when the tri-exponential, cooperative model is used as this model transfers 30-40 mV to electrostatically dominated interaction potentials. The overall electron transfer pattern can be related to the recently determined crystal structure of the F! stutzeri cytochrome c,.Keywords. Electron transfer; cytochrome c4 ; bandshape resolution ; cooperativity.Multi-centre metalloproteins or protein complexes are a dominating feature in respiratory and photosynthetic electron transfer (ET) 11-41. One functional implication of this is that close and specific mutual orientation of individual metallic ET centres ensures facile long-range directional ET by favourable electronic coupling [3]. In addition, electric field changes associated with a given ET step may induce electrostatic or conformational changes in other centres, poising the latter for favourable subsequent ET in a cooperative multi-centre ET pattern [5-91. Long-range ET features relating to the donor-acceptor electronic coupling and energy gap have been broadly investigated [3, 4, 10-141. Well characterized cases of multicentre ET cooperativity are much more limited and probably restricted to the four-heme cytochromes (cyts) c,. These have been functionally mapped in great detail 15-8, 15, 161 and elements of a theoretical ET frame suggested [9]. Two-centre proteins offer attractive alternatives towards cooperative ET mapping due to the much smaller number of interactions. Compared with fourcentre proteins, the maximum number of microscopic reduction potentials is thus reduced from 32 to four and the number of rate cons...

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