The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

Following subcutaneous inoculation of newborn Wistar-Furth rats with human adenovirus type 9 (Ad9), 16 of 16 female and 0 of 11 male rats developed mammary tumors. Tumor-positive animals usually developed tumors in multiple glands. Histopathological analyses indicated that three general categories of tumor could be identified. Mammary fibroadenomas were the most common tumor type encountered, but phyllodeslike tumors and solid sarcomas were also frequently found. In situ hybridization and immunohistochemical techniques established that benign fibroadenomas were derived from mammary fibroblasts (collagen type I-and vimentin-positive cells) and that malignant tumors were derived from myoepithelial cells (collagen type IV-, vimentin-, and muscle-specific actin-positive cells). The fact that mammary tumors were limited to female rats suggested that female hormones are essential for tumor growth and development. In this regard, ovariectomy of Ad9-infected female rats prevented tumor development, while subsequent diethylstilbestrol (DES) treatment elicited tumor formation. In addition, Ad9-infected and castrated male rats which received DES also developed mammary tumors. Established male mammary tumors regressed when DES treatment was stopped and reappeared after DES treatment was resumed. Together, these results indicate that estrogen is required for both initiation and maintenance of Ad9-induced mammary tumors. Southern blot analysis of high-molecularweight tumor DNA showed that mammary tumor cells contained single or multiple integrated copies of the entire Ad9 genome. RNase protection experiments established that estrogen receptor as well as Ad9 Ela and E4 mRNAs were expressed in mammary tumors, but Ad9 E3 and, surprisingly, Elb mRNAs were not expressed at detectable levels.

Of 135 kidney allograft recipients twenty one {15-5°/Q) developed a total of 84 malignant skin tumours from 4 to 115 months after transplantation. Seven of these patients also developed a total of 12 keratoacanthomas. Skin lesions due to viral, fungal and opportunistic organisms were prevalent hut serious pyogenic skin infections were not increased.In contrast, of 50 patients on immunosuppressive therapy for glomerulonephritis or collagen diseases, only two had skin tumours ; none of which were squamous cell carcinomas.

1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine methyl ester (L-NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model. 2. Two groups of SHR (n = 8) with streptozotocin-induced diabetes were studied. One group was given L-NAME 5 mg/kg bodyweight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay. 3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L-NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 +/- 2.9 compared with 6.5 +/- 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001). 4. Systolic blood pressure was significantly elevated in the L-NAME group throughout the study compared with the control group. 5. Plasma AngII was significantly elevated in the L-NAME group compared with controls (42.8 +/- 10.3 vs 15.1 +/- 1.9 pmol/L, respectively; P < 0.05). 6. Activation of the renin-angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.

This paper describes a newborn with a number of clinical manifestations compatible with duplication 16p due to a 46, XY, -7, +der (7), t(7;16) (p22;p13) pat karyotype. In addition, the baby had chondrodysplasia punctata, whose distribution of lesions did not match any of the well-documented forms of these disorders. The baby also had microcornea and lacked a gallbladder, two features, in addition to chondrodysplasia punctata, that have not previously been noted in cases of duplication 16p.

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The effect of testosterone propionate (TP), alone and in combination with porcine GH, on the growth of hypophysectomized rats was investigated. An initial study determined doses of TP and GH which would result in a synergistic response. Hypophysectomized male rats, approximately 40 days of age, received GH at doses of 5, 25 and 62.5 micrograms/day administered in two injections/day at 08.00 and 16.00 h. At all doses of GH, administration of TP at 100 micrograms/day significantly enhanced the GH-stimulated rate of growth. This growth enhancement by TP was greatest in combination with GH at 25 micrograms/day. In a subsequent study, growth responses to 25 micrograms GH/day and 100 micrograms TP/day were examined in animals with differing degrees of sexual differentiation. Sex groups were: intact males, males castrated at 11 days of age and females administered 100 micrograms TP at 3 days of age (masculinized rats), and males castrated at 2 days of age and normal females (non-masculinized rats). In all sex groups, growth of hypophysectomized rats was stimulated by GH. Genetic sex and masculinization did not influence the response to GH. Masculinized hypophysectomized rats exhibited significantly greater rates of growth and final live, empty body, liver and kidney weights than non-masculinized hypophysectomized rats. All sex groups other than normal females responded synergistically to the combination treatment of GH plus TP. Rats that experienced neonatal exposure to testosterone became programmed to respond to testosterone and demonstrated greater rates of growth and body and organ weights when administered the combination of GH plus TP. These data indicate that TP synergizes with GH to promote growth of hypophysectomized rats appropriately programmed to respond.(ABSTRACT TRUNCATED AT 250 WORDS)

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