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Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure–activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7S,8R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7S,8R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7S,8R)-27a and 51b as n...

Background in psychophysics Psychophysical experiments have shown that the human brain has a natural preference for harmonic sounds and relationships between musical tones. Even naïve listeners are able to distinguish harmonic from inharmonic musical intervals and, under many conditions, the pitches of octaves are confused even though their fundamental frequency differs by a factor of two. Our psychophysical investigations in Mongolian gerbils have shown that animals can also learn to differentiate musical intervals. Background in neurophysiology In order to understand pitch perception and the neuronal basis of harmonicity, we have to understand how neurons in the central auditory system process acoustic signals. It has been demonstrated that temporal processing mechanisms in the auditory brainstem are essential for these fundamental aspects of musical perception. Neurophysiological experiments have revealed that the periodicity of signal envelopes is crucial for the perception of pitch. Neuronal representations of envelope periods, which reflect the superposition of partials of harmonic sounds in the cochlea, are analysed by temporal correlation mechanisms in the central auditory system. These mechanisms also include processing of resolved partials. Aims In this paper we attempt to explain pitch perception and our preference for harmonic sounds on the basis of the temporal neuronal analysis and the spatial representation of pitch information in the brain. Conclusions As a result of cochlear analysis, frequency is mapped along a tonotopic axis in all auditory brain areas. Similarly, as a result of temporal analysis, periodicity is mapped from the midbrain to the auditory cortex. In each case, tonotopic and periodotopic axes are orthogonal to each other. One may say that spectral information, as an important aspect of timbre, is mapped along a first neural axis, periodicity (pitch) is mapped along the second neural axis of the auditory system. Finally, as a result of temporal analysis, neurons in the auditory midbrain show preferences for harmonically related sounds. The major function of the ventral nucleus of the lateral lemniscus (VNLL), which seems to have a structure reminiscent of the pitch helix of music psychology, appears to be to control and suppress these harmonic responses.

The iridoid alkaloid gardenamide A (3) was isolated from the phytochemically uninvestigated East African Rubiaceae species Rothmannia urcelliformis (Hiern) Bullock. Its absolute stereostructure was determined by quantum chemical CD calculations, which constitutes the first application of this useful chiroptical tool within the class of iridoids. An additional stereochemical proof succeeded by its biomimetic partial synthesis starting from the well-known nitrogen-free iridoid genipine (1).

Configurationally unstable biaryl lactones of type (M)-1 ⇌ (P)-1 and ring-opened 2-acyl-2‘-hydroxy biaryl compounds of type (M)-4 ⇌ (P)-4 are versatile precursors for the atroposelective preparation of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched material for smaller interconversion rates. For the lactones, the free activation energies ΔG⧧298 increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe (t1/2 ≈ ms) < Me (t1/2 ≈ s) < Et < i-Pr (t1/2 ≈ min) < t-Bu (t1/2 ≈ d). The formally ring-opened 2-acyl-2‘-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of the high loss in acti...

The total synthesis of the N-quaternary isoquinoline alkaloid gentrymine B (1) and of its unnatural enantiomer as well as its oxidative degradation is described. A further proof of stereostructure and hints at the biosynthetic origin of the unusual S,S-configuration in gentrymine B (1) were obtained by an additional biomimetic synthesis of 1 from the related—but 1R-configured—natural product gentrymine A (2), by N-methylation and subsequent spontaneous epimerization at C-1.

From the leaves of Burchellia bubalina (Rubiaceae) pure P- and a-gardiol have been isolated, the latter in crystalline form for the first time. X-ray analysis of P-gardiol establishes its relative configuration. Treatment of the tosyl derivative of P-gardiol with base affords a crystalline elimination product amenable to X-ray analysis. Evidence is presented for the partial conversion of a-gardiol to the epimeric P-gardiol at room temperature. Molecular dynamic studies at 1000 K on the two gardiols provide useful conformational information. In the case of P-gardiol, the analysis shows interesting correlations between conformations adopted at 1000 K and those present in the crystalline state at room temperature.

The first synthesis of an N-quaternary salt of a naphthylisoquinoline alkaloid, N,N-dimethyldioncophyllinium A iodide, is described. For this potential natural product, a degradative procedure for the unambiguous stereoanalysis of the stereogenic centers has been elaborated. It shows enhanced anti-plasmodial activity in vitro towards Plasmodium falciparum erythrocytic forms, as compared to its less methylated precursors.

In the forebrain, synaptic glycine concentrations are regulated through the glycine transporter GlyT1. Because glycine is a coagonist of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), which has been implicated in schizophrenia, inhibition of GlyT1 is thought to provide an option for the treatment of schizophrenia. In support of this hypothesis, GlyT1 inhibitors facilitate in vivo NMDAR function and demonstrate antipsychotic-like effects in animal models. Among the specific GlyT1 inhibitors, substituted N-methyl-glycine (sarcosine) derivatives (e.g., (R)-N[3-(4'fluorophenyl)-3-(4'phenyl-phenoxy)propyl]-sarcosine [NFPS], (R)-N[3-phenyl-3-(4'-(4-toluoyl)phenoxy)-propyl]sarcosine [(R)-NPTS], and (R,S)-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine [Org24589]), and non-sarcosine-containing inhibitors, such as 2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734), have been described. In the present study, we analyzed the mode of interaction of these compounds with GlyT1 by using electrophysiological measurements in Xenopus laevis oocytes, and with two binding assays, using [(3)H](R)-NPTS or 2-chloro-N-[(S)-phenyl[(2S)-N-methylpiperidin-2-yl]-methyl]-3-trifluoromethyl benzamide monohydrochloride ([(3)H]N-methyl-SSR504734) as radioligands. Inhibition of electrogenic glycine transport by sarcosine-based compounds was apparently irreversible and independent of glycine concentration. The latter indicates a noncompetitive mode of action. In contrast, both SSR504734 and N-methyl-SSR504734 exhibited reversible and competitive inhibition of glycine transport. In GlyT1-expressing membranes, the binding of the novel radioligand [(3)H]N-methyl-SSR504734 to a single site on GlyT1 was competitively displaced by glycine and SSR504734 but noncompetitively by sarcosine-based compounds. Inversely, [(3)H](R)-NPTS binding was competitively inhibited by sarcosine-based compounds, whereas glycine, SSR504734, and N-methyl-SSR504734 noncompetitively decreased maximal binding. Our data indicate that besides exerting an apparently irreversible or reversible inhibition, GlyT1 inhibitors differ by exhibiting either a noncompetitive or competitive mode of inhibition. The divergent modes of inhibition may significantly affect the efficacy and tolerability of these drugs.

In diesem Kapitel wird ein neuronales Modell zur Verarbeitung von Schallsignalen eingefuhrt. Das Periodizitats-Analyse-Netzwerk (PAN) ist ein bioinspiriertes neuronales Netzwerk spikender Neurone. Das PAN besteht aus komplexen neuronalen Modellen, die fur die Untersuchung der Dynamik von einzelnen Neuronen und neuronalen Netzen benutzt werden konnen. Das Netzwerk kann Eigenschaften der Grundfrequenz von harmonischen Schallsignalen verarbeiten. Daher kann das PAN-Modell in klassischen schallverarbeitenden Anwendungen eingesetzt werden, wie z.B. zur Trennung von Schallquellen, zur Periodizitatsanalyse und zur Losung des Cocktail-Party-Problems.

The isolation of 6-hydroxyluteolin-7-O-(1"-alpha-rhamnoside) from the Central American epiphyte Vriesea sanguinolenta Cogn. and Marchal (Bromeliaceae) is described here. Its stereostructure was established by spectroscopic methods and an X-ray structure analysis of its hepta-O-acetyl derivative. This flavonoid glycoside had previously been reported from some Teucrium species (Labiatae), yet without sufficient physical data and spectroscopic evidence.

The stereoselective total synthesis of the antimalarial korupensamines A (1a) and B (1b) by application of the "lactone method" is described. Key steps of this first atropo-selective access to 5,8'-coupled naphthylisoquinoline alkaloids were the regioselective intramolecular coupling of ester 8 to give the configurationally labile lactone-bridged biaryl 9 and its atropisomer-selective cleavage with a variety of chiral and achiral H-nucleophiles, yielding the configurationally stable P-diol 10a or, optionally, the M-product 10b. From the axially chiral phenylisoquinolines thus obtained atropo-diastereodivergently, the authentic natural naphthylisoquinolines with the respective axial configurations, korupensamines A (1a) and B (1b), were obtained by completion of the second naphthalene ring, starting from the previous "bridgehead" C1 unit.