Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor.

In the present article, we summarize the preclinical pharmacology of 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327), a highly potent and selective agonist of the δ-opioid receptor. AZD2327 binds with sub-nanomolar affinity to the human opioid receptor (K(i) = 0.49 and 0.75 nM at the C27 and F27 isoforms, respectively) and is highly selective (>1000-fold) over the human µ- and κ-opioid receptor subtypes as well as >130 other receptors and channels. In functional assays, AZD2327 shows full agonism at human δ-opioid receptors ([(35)S]GTPγ EC(50) = 24 and 9.2 nM at C27 and F27 isoforms, respectively) and also at the rat and mouse δ-opioid receptors. AZD2327 is active in a wide range of models predictive of anxiolytic activity, including a modified Geller-Seifter conflict test and social interaction test, as well as in antidepressant models, including learned helplessness. In animals implanted with microdialysis probes and then given an acute stressor by pairing electric shock delivery with a flashing light, there is an increase in norepinephrine release into the prefrontal cortex associated with this acute anxiety state. Both the benzodiazepine anxiolytic standard diazepam and AZD2327 blocked this norepinephrine release equally well, and there was no evidence of tolerance to these effects of AZD2327. Overall, these data support the role of the δ-opioid receptor in the regulation of mood, and data suggest that AZD2327 may possess unique antidepressant and anxiolytic activities that could make a novel contribution to the pharmacotherapy of psychiatric disorders.

2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.

MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.

[Synovial sarcoma of the neck]. / Miesak maziówkowy szyi.

Authors described the case of synovial sarcoma of very rare neck localization. The starting point of the tumor was most likely bursa synovialis between the hyoid bone and ligament thyreo-hyoid. The occurrence and progress of the synovial sarcoma was also presented on the basis of literature.

[Combined modality treatment with chemotherapy followed by surgery with immediate reconstruction and irradiation for primary unresectable oral cavity cancer]. / Ocena tolerancji indukcyjnej chemioterapii, leczenia operacyjnego z natychmiastowa rekonstrukcja i uzupelniajacej radioterapii u chorych na pierwotnie nieoperacyjnego raka jamy ustnej.

In the Head and Neck Cancer Department of Cancer in Warsaw between August 1997 and September 1998 twenty patients with primary unresectable oral cavity cancer were referred for combined modality treatment with cisplatin based chemotherapy followed by wide resection (in the case of tumor regression) with immediate reconstruction and adjuvant radiotherapy. Tumor regression after chemotherapy was obtained in 15 patients and all of them were referred to surgery; wide resection and reconstruction using pectoralis major (PM) flap. 14 patients completed all treatment protocol, also with adjuvant radiotherapy. Tolerance of treatment was excellent and there was no influence of chemo- and radiotherapy for adaptation of PM flaps. During observation local recurrence was observed in two cases. Twelve patients are alive without evidence of disease. Study is continued.

[The effects of anti-inflammatory treatment in patients treated with chemotherapy for advanced head and neck cancer]. / Efekty leczenia przeciwzapalnego u chorych leczonych cytostatykami z powodu nowotworu regionu glowy i szyi.

The aim of the study is to analyse the effect of anti-inflammatory treatment in patients treated with chemotherapy for advanced head and neck cancer. 110 patients treated in the Head and Neck Department in CO in Warsaw were entered to study. Pain, dyspnoea, inflammatory reaction foetor ex ore, fever were assessed. Clinical response was positive in 67% of patients, microbiological improvement was positive in 44% and subjective response in 68% of patients.

Effects of the δ opioid agonist AZD2327 upon operant behaviors and assessment of its potential for abuse.

AZD2327 is a brain-penetrant agonist at δ opioid receptors which has antidepressant and anxiolytic properties in a wide array of animal models. As part of the preclinical safety pharmacology assessment, a number of studies were conducted in order to characterize its behavioral effects and its potential for abuse, in order to enable testing in humans. AZD2327 produced only modest effects when tested in a multiple fixed-ratio differential reinforcement of low rate schedule in rats, and did not enhance the rate-suppressing effects of ethanol in the procedure. In a suppressed responding test, AZD2327 only reduced rates of unpunished responding. In drug discrimination studies, AZD2327 produced partial or no generalization from known drugs of abuse. In primates trained to self-administer cocaine, substitution with AZD2327 did not result in appreciable self-administration of AZD2327, indicating that it does not behave as a positive reinforcer under the present conditions. Following termination of repeated administration of AZD2327, no signs of physical dependence (withdrawal) were noted. Overall, the data suggest that AZD2327 does not possess a high potential for abuse, and appears to have only subtle behavioral effects as measured by operant behaviors.

Metabolic rate and thyroid activity of hens in relation to the state of feathering.

Heat production, rectal temperature and thyroid activity were determined in NH X Lg hens that were 40 and 80% defeathered. Within individual groups there was a significant increase in heat production only in hens that were 80% defeathered. In comparison with the control group, defeathered chickens had higher metabolic rates during each examined period. During the third week of the experiment there was a temporary drop in the rectal temperature of the experimental birds. After nine weeks chicken with the greatest degree of defeathering had the highest thyroid weight and the highest levels of thyroxin in the blood plasma.

Effect of methanabol (17 beta hydroxy-17 alpha methyl-1,4-androstadiene-3-one) on growth and breast muscle nucleic acid content in the chicken.

1. The effect of methanabol (17 beta hydroxy-17 alpha methyl-1,4-androstadiene-3-one) on growth and breast muscle nucleic acid in White Rock chickens grown to 8 weeks of age was tested. Methanabol was administered by mouth daily during this period at 0.05 mg/kg body weight in aqueous suspension to 30 birds, with appropriate controls. 2. Growth was significantly increased by methanabol. 3. Breast muscle RNA was significantly increased by methanabol but DNA was not affected.

The effect of short term thermal stress on the heart and respiration rates of conscious and anaesthetized chickens.

Heart and respiration rates were measured in eight 6-week-old, White Rock chicks at different ambient temperatures: 24--26 degrees C (neutral), 6.5--8.5 degrees C (low) and 3,95--43.5 degrees C (high). The animals were exposed to these temperatures for 10 min. In both groups the low ambient temperature did not influence the respiration rate, whereas the high temperature caused a significant increase of the respiration rates both in the conscious and anaesthetized birds. In both groups no significant changes in the heart rate at different temperatures were found. Statistically significant differences in the heart and respiration rates between the conscious and anaesthetized chickens were noted only at the low environmental temperature.

Effect of sodium chloride deficiency on basal metabolism in broiler chickens.

1. Male broiler chickens were given a sodium chloride-deficient or NaCl-adequate diet from 7 to 21 d of age in Expt 1 and 28 to 56 d of age in Expt 2. 2. NaCl-deficient chickens had a markedly poorer growth and food conversion efficiency than those given the NaCl-adequate diet. 3. NaCl deficiency was associated with an increase in basal metabolic rate and increases in oxygen consumption, heat production and respiratory quotients were also noted. The glycogen content of chicken livers was also higher. 4. MEasurements of acid-base balance were found to be changed in NaCl-deficient chickens. Values for pH and bicarbonate content in blood plasma were lowered. 5. NaCl deficiency increased the packed cell volume and thyroxine level in blood plasma. Sodium and chloride contents in blood were lowered. 6. Results are discussed in relation to the decreased food conversion in NaCl-deficient chickens.

Statistical evidence that endogenous reverse triiodothyronine (rT3) may affect oxygen consumption in food deprived chickens.

Exogenous rT3 decreases O2 consumption in mammals and birds. Until now a correlation coefficient and a regression equation have not been presented. Statistical evaluation seems to be requisite for verifying the answer to the question of whether endogenous rT3 may be able to reduce O2 consumption in birds where the normal level of plasma rT3 is 10 times less than the corresponding level of T3. Food deprived chickens (for 48 h) were used in this study because fasting enhances plasma rT3. The results revealed a reciprocal relation of T3 and rT3 in the circulation. Reverse T3 began to increase when T3 decreased to a plateau at 53.9% of initial level. As expected a reciprocal relationship was obtained (r = -0.749; n = 36) between plasma rT3 and O2 consumption. The regression line was calculated according to the equation: Y = -0.388X + 0.856. This relation differs from the linear relationship between T3 and O2 consumption (r = 0.796; Y = 0.107X + 0.449). The regression line lies in the range of 0.122-0.778 nmol rT3/l, which is found in some physiological conditions in birds where elevated plasma rT3 occurs. This suggests that endogenous rT3 may participate in modifying O2 consumption in birds. Using the rT3:T3 ratio the correlation coefficient was somewhat higher (r = -0.831; Y = -0.673X + 0.831) suggesting common involvement of both triiodothyronines in the reduction of O2 consumption during food deprivation. The drop in O2 consumption after 48 h of food deprivation was 28.4%; decreased T3 and increased rT3 may participate in 15.4% and 13.0% of this fall, respectively. The hypometabolic effectiveness of rT3 seems to be greater than the hypermetabolic effectiveness of T3, since a smaller increase of plasma rT3 was needed to reduce O2 consumption compared to the amount of T3 necessary to enhance it.

Hypometabolic effect of 3,3',5'-triiodothyronine in chickens: interaction with hypermetabolic effect of 3,5,3'-triiodothyronine.

The effect of 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine (T3) on O2 consumption in 1-day-old chickens was studied. The birds were divided into five groups, each of six chickens: (1) control--without injection; (2) control--injected with 100 microliters of solvent (0.01 N NaOH in saline); (3) injected with 10 micrograms rT3/chicken; (4) injected with 0.5 micrograms T3/chicken; and (5) injected with 10 micrograms rT3 + 0.5 microgram T3/chicken. O2 consumption was measured using a Kipp & Zonen diaferometer at neutral temperature (30 degrees) 0, 1, 2, 3, and 4 hr after injection of hormones. Corresponding groups of other chickens served only for blood collection. rT3 and T3 were measured by radioimmunoassay. Reverse T3 decreased O2 consumption by 10.87%. Contrary to this, T3 increased O2 consumption by 29.41%. Reverse T3, injected together with T3, interacted with the hypermetabolic effect of T3 up to 2 hr after injection; then, O2 consumption started to increase, and was about 16.7% higher compared with the basal level 3 hr after injection. The blood plasma level of rT3 increased about 29-fold at the first hour after injection, without changes in the basal level of T3. Administration of T3 increased its level 6-fold 2 hr after injection, which was accompanied by a gradual decrease in the basal level of rT3 (3.7-fold) 4 hr after injection. Administration of rT3 + T3 increased the rT3 level 30-fold at 2 hr and the T3 level 1.7-fold at the first hour after injection. Thus, rT3 acts hypometabolically and interacts with the hypermetabolic effect of T3; administration of T3 lowered the basal level of rT3; and the plasma level of T3 did not change after administration of rT3.