Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.     

Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists

A new series of cysLT₁ receptor antagonists represented by CP-288,886 (7) and CP-265,298 (8) were developed which are equipotent to clinical cysLT₁ receptor antagonists Zafirlukast (1) and Pranlukast (2).     

Genetic control of scrapie and Creutzfeldt-Jakob disease in mice

Genetic control of experimental scrapie and Creutzfeldt-Jakob disease (CJD) was studied in inbred strains of mice by measuring the times from intracerebral inoculation with the agents to the onset of neurological dysfunction. Every strain of mice examined was susceptible to infection; however, a wide range of incubation times was found for both scrapie and CJD. New Zealand (NZ) mice, which eventually develop an autoimmune disorder, were inoculated intracerebrally with 10(6) ID50 units of the scrapie agent in a Chandler isolate. NZW mice showed incubation periods of less than 95 days; this is the shortest period recorded for any murine host with scrapie. In NZB and NZB X W F1 mice, the incubation periods were approximately 130 days and were similar to those in BALB/c and C57BL mice. Male and female NZ mice exhibited scrapie incubation periods of the same length. Similar results were obtained when B10.Q and C57BL/6J mice were inoculated intracerebrally with 10(4) ID50 units of the CJD agent in a K.Fu. isolate. These observations define a genetic locus or loci controlling the length of scrapie and CJD incubation periods; alleles coding for longer incubation times appear to be autosomal dominant. When congenic mice with a C57BL/10J background differing only in their H-2 haplotypes were studied, the results showed that the D subregion of the H-2 complex played a central role in controlling the length of the CJD incubation period. The q allele at the D subregion resulted in shorter incubation times, whereas the d allele resulted in long incubation times. The p, s, b, and k alleles gave intermediate incubation times. We propose the symbol PID-1 for designating this genetic locus which is located within the D subregion of the major histocompatibility (H-2) complex on murine chromosome 17. In addition, observations on congenic mice provide evidence for the influence of sex on CJD incubation periods. In some strains of inbred mice, males showed significantly shorter incubation periods compared with those for females with experimental CJD. These studies with inbred mice have defined previously unrecognized genes that control the length of scrapie and CJD incubation periods.     

Development of Flat and Fan-Shaped Fruit in Actinidia chinensis var. chinensis and Actinidia deliciosa

We describe and quantify development of flat and fan-shapedfruit of Actinidia chinensis var. chinensis from inception tomaturity. Flat fruit arise from particularly large and flatfloral meristems. After bract initiation, the terminal flowerremains elliptic in cross section, produces elliptic whorlsof floral organs, and forms a flat-shaped ovary. The allometryof the ovary does not change from inception to maturity. Fan-shapedfruit develop from exceptionally flat floral meristems. Theyresult from postgenital fusion of the terminal flower with oneor two precocious lateral flowers. Timing of the fusion processvaries, resulting in a variable degree of integration of tissues.The fasciated flower has supernumerary floral organs, and isborne on a single pedicel. The histology of mature flat andfan-shaped fruit is described for commercially-grown Actinidiadeliciosa cv. Hayward. Mature flat fruit have a larger maximumdiameter, but are comparable to normal fruit in the minimumdiameter. Flat fruit have more locules and more pericarp tissuethan normal fruit, but these are not causally related to fruitshape. The flat shape can be attributed to differential planesof enlargement of cells in certain regions of the central core.Mature fan-shaped fruit are larger, and have more pericarp,core and locules than normal or flat fruit.Copyright 1994, 1999Academic Press Actinidia chinensis, Actinidia deliciosa, fruit shape, development, anatomy, fusion