The thickness of erector spinae muscles can be easily measured by computed tomography for the assessment of physical activity: An observational study.

The loss of muscle mass and changes in muscle composition are important factors for assessing skeletal muscle dysfunction. The cross-sectional area (CSA) of muscle is usually used to assess skeletal muscle function. However, the CSA of skeletal muscle can be difficult for clinicians to measure because a specific 3D image analysis system for computed tomography (CT) scans is needed. Therefore, we conducted a study to develop a new method of easily assessing physical activity, in which the thickness of the erector spinae muscles (ESMT) was measured by CT, and to compare ESMT to the CSA of the erector spinae muscles (ESMCSA) in patients with nontuberculous mycobacteria (NTM) pulmonary infections who underwent surgery after some preoperative examinations, such as laboratory tests, chest CT scans, spirometry, and 6-minute walk tests (6MWT). We retrospectively studied adult patients with NTM pulmonary infections who underwent a lobectomy at Fukujuji Hospital from April 2010 to March 2016. We assessed the correlations between ESMT and different variables, including ESMCSA. Sixty-one patients with NTM pulmonary infections were included. The median ESMT and ESMCSA were 1371 mm2 (IQR 1178-1784 mm2) and 28.5 mm (IQR 25.4-31.7 mm), respectively, and a very strong linear correlation was observed between ESMT and ESMCSA (R = 0.858, P < .001). ESMT and ESMCSA were positively associated with body weight (ESMT: R = 0.540, P < .001, ESMCSA: R = 0.714, P < .001), body mass index (ESMT: R = 0.421, P < .001, ESMCSA: R = 0.560, P < .001), the 6MWT value (ESMT: R = 0.413, P = .040, ESMCSA: R = 0.503, P = .010), vital capacity (ESMT: R = 0.527, P < .001, ESMCSA: R = 0.577, P < .001), and the forced expiratory volume in 1 second (ESMT: R = 0.460, P < .001, ESMCSA: R = 0.532, P < .001). We demonstrated that compared to ESMCSA, ESMT is easily measured by CT and can be a useful parameter for clinically evaluating physical activity. Furthermore, ESMT and ESMCSA were related to physical activity, as measured by the 6MWT and spirometry.

In-hospital pulmonary rehabilitation after completion of primary respiratory disease treatment improves physical activity and ADL performance: A prospective intervention study.

INTRODUCTION: Pulmonary rehabilitation improves the physical condition of patients with chronic respiratory disease; however, there are patients who cannot leave the hospital because of their low activities of daily living (ADLs), despite the completion of primary respiratory disease treatment and rehabilitation during treatment. Therefore, this study demonstrated that those patients recovered their ADLs through in-hospital pulmonary rehabilitation after treatment completion. METHODS: We prospectively studied 24 hospitalized patients who had some remaining symptoms and showed low ADL scores of 9 points or less on the short physical performance battery after undergoing treatment for respiratory disease in Fukujuji Hospital from October 2018 to October 2019, excluding 2 patients who had re-exacerbation and 1 patient who could not be examined using the incremental shuttle walk test (ISWT). After completion of the primary respiratory disease treatment, patients moved to the regional comprehensive care ward, and they received pulmonary rehabilitation for 2 weeks. In the ward, patients who could not yet leave the hospital could undergo pulmonary rehabilitation for up to 60 days. Data were evaluated three times: upon treatment completion (baseline), postrehabilitation, and 3 months after baseline. The main outcome was an improvement in the incremental shuttle walk test (ISWT) postrehabilitation. RESULTS: The median age of the patients was 80 (interquartile range (IQR): 74.8-84.5), and 14 patients (58.3%) were male. The ISWT distance significantly increased postrehabilitation (median [IQR]: 60 m [18-133] vs 120 m [68-203], P < .001). The Barthel Index (BI) (P < .001), the modified Medical Research Council (P < .001), and other scale scores were also improved. Among patients with acute respiratory diseases such as pneumonia, chronic obstructive pulmonary disease, and interstitial pneumonia, ISWT and other data showed improvement at the postrehabilitation timepoint. Ten patients who could perform examinations at 3 months after baseline were evaluated 3 months after taking baseline data prior to starting rehabilitation. The ISWT showed significant improvement 3 months after baseline compared to baseline (P = .024), and the ISWT distance was maintained after rehabilitation. DISCUSSION AND CONCLUSIONS: Physical activity, symptoms, mental health, and ADL status in patients who had not recovered after primary treatment completion for respiratory diseases could improve through in-hospital pulmonary rehabilitation.

Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice.

We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

Anti-emetic effect of mosapride citrate hydrate, a 5-HT4 receptor agonist, on selective serotonin reuptake inhibitors (SSRIs)-induced emesis in experimental animals.

Although selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, they frequently cause gastrointestinal adverse effects, such as nausea and emesis. In the present study, we investigated the anti-emetic effect of mosapride, a 5-HT(4) receptor agonist, on SSRIs-induced emesis in Suncus murinus and dogs. We also examined the effect of mosapride on SSRIs-induced delay in gastric emptying and increase in gastric vagal afferent activity in rats. Oral administration of paroxetine, but not its subcutaneous administration, dose-dependently caused emesis in both animals. Mosapride inhibited paroxetine-induced emesis in Suncus murinus and dogs with ID(50) values of 7.9 and 1.1 mg/kg, respectively. The anti-emetic effect of mosapride was partially inhibited by SB207266, a selective 5-HT(4) antagonist. Intragastric administration of paroxetine increased gastric vagal afferent discharge in anesthetized rats. Mosapride failed to suppress this increase. On the other hands, mosapride improved the delay in gastric emptying caused by paroxetine in rats. We have shown in this study that oral administration of SSRIs causes emesis and activates gastric vagal afferent activity in experimental animals and that mosapride inhibits SSRIs-induced emesis, probably via improvement of SSRIs-induced delay in gastric emptying. These findings highlight the promising potential of mosapride as an anti-emetic agent.

Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension-induced visceromotor response in conscious rats.

Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold.

The possible involvement of dopamine D3 receptors in the regulation of gastric emptying in rats.

AIM: The inhibitory effect of dopamine on gastric motility is thought to be mediated via a decrease in acetylcholine release resulting from stimulation of enteric neuronal dopamine D(2) receptors. The aim of this study was to investigate the possible involvement of the dopamine D(3) receptor in the regulation of gastric motility in rats using selective dopamine D(3) receptor agonists or a dopamine D(3) receptor antagonist. MAIN METHODS: Gastric emptying was assessed using the phenol red method after rats were treated with varying doses of dopamine D(3) receptor agonists or a dopamine D(3) receptor antagonist. KEY FINDINGS: S(+)-PD 128,907 (0.01-1 mg/kg, s.c.), a selective dopamine D(3) receptor agonist, dose-dependently delayed gastric emptying in rats. Other dopamine D(3) receptor agonists (i.e., R(+)-7-OH-DPAT [0.03-1 mg/kg, s.c.] and quinpirole [0.01-1 mg/kg, s.c.]) also delayed gastric emptying in rats. Both the selective dopamine D(1) and D(5) receptor agonist SKF-38393 and the selective dopamine D(4) receptor agonist PD 168,077 failed to delay gastric emptying in rats. The selective dopamine D(3) receptor antagonist (+)-S 14297 (10mg/kg, s.c.) partially inhibited the S(+)-PD 128,907-induced delay in gastric emptying. Although an administration of S(+)-PD 128,907 (1-100 µg/kg) into the 4th cerebral ventricle partially and dose-dependently delayed gastric emptying in rats, its administration into the lateral cerebral ventricle did not affect gastric emptying. SIGNIFICANCE: The results presented here suggest that peripheral dopamine D(2) receptors and, at least in part, dopamine D(3) and central dopamine D(2)/D(3) receptors play an important role in the regulation of gastric motility in rats.

Effect of mosapride citrate hydrate on the colon cleansing action of polyethylene glycol electrolyte lavage solution (PEG-ELS) in guinea pigs.

Polyethylene glycol electrolyte lavage solution (PEG-ELS) is widely used for colon cleansing prior to colonoscopy and colonic surgery. It has recently been shown that coadministration of PEG-ELS and mosapride citrate hydrate (mosapride), a selective 5-HT(4)-receptor agonist, is clinically useful for barium enema examination as it allows adequate barium coating. However, there is no report showing that mosapride has beneficial effects on colon cleansing and its underlying mechanism in experimental animals. In the present study, we investigated the effects of mosapride on colonic transit and on the colon cleansing action of PEG-ELS in guinea pigs. Mosapride (10 - 20 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs. Although PEG-ELS alone showed adequate colon cleansing action, excess fluid remained in the colon. Coadministration of mosapride (20 mg/kg) and PEG-ELS, regardless of mosapride timing, reduced colonic content weight (dry residue and water amount) as compared to PEG-ELS alone. These findings suggest that mosapride enhances the colon cleansing action of PEG-ELS via an increase in colonic transit in guinea pigs, that is, it reduces not only fecal residue but also excessive fluid in the colonic lumen. It is therefore believed that coadministration of mosapride and PEG-ELS can allow better visualization in barium enema examination.

Clinical factors on cavitary and nodular bronchiectatic types in pulmonary Mycobacterium avium complex disease.

BACKGROUND AND OBJECTIVE: Pulmonary Mycobacterium avium complex (MAC) disease is the most common pulmonary non-tuberculous mycobacteriosis (NTM). The clinical and radiological findings were similar to those of pulmonary tuberculosis, both of which are characterized by upper lobe cavities. On the other hand, the presence of middle and lower field lesions with centrilobular nodules and bronchiectasis has been noted. We analyzed the clinical feature of these two radiologically different types and identified their prognostic factors. METHODS: The clinical, laboratory and radiological findings of 273 cases of MAC disease, newly diagnosed during the recent 7 years periods, were investigated. They were radiologically classified into cavitary (Cav) and nodular bronchiectasis (NB) types at the time of diagnosis. The findings of 44 fatal cases were compared with those of the newly diagnosed cases. RESULTS: A prominent increase in the number of cases was recently found only in females. Low body mass index (BMI) and moderately reduced serum albumin were found at the time of first hospital visit in both newly diagnosed and fatal cases. In the latter, peripheral blood lymphocyte count was slightly decreased, and tuberculin skin test was negative in 57.7% of the cases. Radiologically, Cav type was prevalent in males and NB type in females in the newly diagnosed cases, while in the fatal cases Cav type was frequently found in both males and females. The two radiological patterns did not change during the entire disease course. CONCLUSION: Cav type in females was one of the pathogenetic factors. Deterioration of cell-mediated immunity may underlie MAC disease.

Inhibition of lipase activities by basic polysaccharide.

Basic polysaccharide strongly inhibited the hydrolysis of trioleoylglycerol (TO) emulsified with phosphatidylcholine and taurocholate by either pancreatic lipase or carboxylester lipase. DEAE-Sephadex dose-dependently inhibited the hydrolysis of TO by pancreatic lipase and carboxylester lipase; however, carboxymethyl-Sephadex and Sephadex G-50 did not inhibit the hydrolysis. Polydextrose (PD), a soluble polysaccharide, was a very weak inhibitor of pancreatic lipase. However, when a basic group, a DEAE group, was attached to PD, lipase inhibition by DEAE-PD was increased, and this was dependent on the substitution ratio of DEAE groups. The number of positive charges per PD molecule is important in lipase inhibition. Similar substitution effects were observed with other basic groups, such as piperidinoethyl and 3-triethylamino-2-hydroxypropyl. The natural basic polysaccharide, chitosan, also inhibited pancreatic lipase activity. Gel-filtration experiments suggested that DEAE-PD did not bind strongly to pancreatic lipase. The effect of DEAE-PD on TO hydrolysis by pancreatic lipase was studied using various emulsifiers: DEAE-PD (50 microg/ml) did not inhibit the hydrolysis of TO emulsified with arabic gum, phosphatidylserine, or phosphatidic acid. In vivo, oral administration of DEAE-PD to rats reduced the peak plasma triacylglycerol concentration and increased fecal lipid excretion. These results suggest that basic polysaccharide is able to suppress dietary fat absorption from the small intestine by inhibiting pancreatic lipase activity.

Exercise training for the improvement of exercise performance of patients with pulmonary tuberculosis sequelae.

OBJECTIVE: To examine whether exercise training using nontreadmill walking is effective for the improvement of exercise performance of patients with pulmonary tuberculosis sequelae (PTS) characterized by restrictive ventilatory defect. PATIENTS AND METHODS: Fourteen patients with stable PTS hospitalized for assessment of exertional dyspnea in Fukujuji Hospital from April 1997 to March 1999 were enrolled in this observational study. All patients underwent baseline pulmonary function tests, arterial blood-gases analysis and exercise tests for initial assessment. Four patients were excluded because of hypoxemia during the initial treadmill test. The remaining 10 patients who stopped exercising because of symptom limitations became candidates for the exercise training. The patients were instructed to perform daily walking exercise training in a hallway in the hospital for 2 weeks. The training was started at their maximum walking speeds during the treadmill test, and walking speed was gradually increased as the patients gained confidence. After finishing the exercise training, the patients performed pulmonary function tests, arterial blood-gases analysis was done, and exercise tests were conducted in identical fashion to the baseline protocol. RESULTS: There were no significant changes in pulmonary function tests and arterial blood-gases analysis after the exercise training. Exercise tolerance improved with a significant increase in peak oxygen uptake (from 13.6+/-2.8 to 14.8+/-2.8 ml/kg/min, p<0.01) and distance covered in a 6-minute walk (from 399+/-62 to 467+/-65 m, p<0.01) after the exercise training. CONCLUSION: The exercise training we conducted is shown to be a safe and effective modality for the improvement of exercise performance of patients with PTS.

Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid.

In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.

Continuous muscle stretch prevents disuse muscle atrophy and deterioration of its oxidative capacity in rat tail-suspension models.

OBJECTIVE: The purpose of this study was to evaluate the effect of continuous muscle stretch on disuse-atrophied muscles. DESIGN: Sprague-Dawley rats were used and divided into five groups: control group, hind limb suspended for 3 and 7 days, and hind-limb suspension plus strenuous continuous muscle stretch for 3 and 7 days. In the hind-limb suspension plus strenuous continuous muscle stretch groups, the gastrocnemius-plantaris-soleus muscles were stretched using a plastic plate that immobilized the ankle joint at the maximum dorsal flexed position during the hind-limb suspension period. The intracellular energy metabolism of the working muscle during electric stimulation was evaluated by phosphorus-31 magnetic resonance spectroscopy in vivo. Changes in phosphocreatine, inorganic phosphate, and the intracellular pH were monitored to evaluate intramuscular oxidative capacity. Maximum tension and muscle wet mass were also measured. RESULTS: The oxidative capacity, muscle wet weight, and maximum tension decreased after hind-limb suspension. The muscle oxidative capacity at control levels was maintained during the first 3 days in muscles subjected to continuous strenuous stretch. It was also effective to prevent the decrease in muscle mass and maximum twitch tension during the initial 3 days. However, the effects did not persist. CONCLUSION: Continuous strenuous stretch was effective to prevent disuse muscle atrophy and its functional deterioration; however, its effects did not last long.

Muscular oxidative capacity in ovariectomized rats discussion on the endurance performance of female athletes with sports-related-amenorrhea.

The purpose of this study was to evaluate the effects of ovariectomy on intramuscular energy metabolism in adult rats. Based on the results, we discussed the skeletal muscle metabolism in female athlete with sports related amenorrhea. Twenty-five adult (20-week-old) Sprague-Dawley female rats were used. Fifteen rats underwent ovariectomy (OVX group), and the other ten rats were sham-operated (Sham group). One and four weeks after surgery, muscular oxidative capacity was measured using (31)P-MR spectra of the gastrocnemius-plantaris-soleus (GPS) muscles group at rest and during electric stimulation. Wet weight and maximum tension of the whole GPS muscles group were also measured. From the MRS measurements, the muscle oxidative capacity in the OVX group was significantly lower than that in the Sham group (p < 0.05) at both one and four weeks after surgery. The muscle's wet weight one week after surgery in the OVX group was the same as the Sham group, while four weeks after surgery it was significantly greater than that in the Sham group (p < 0.05). There were no significant differences in maximum tension among the groups. In conclusion, in adult rats the oxidative capacity decreased due to ovariectomy despite the increase in muscle weight. It is suggested that the muscular endurance capacity in female adult athletes with sports related amenorrhea may deteriorate. Key PointsIn vivo measurement of muscular energy metabolism.Effects of ovariectomy on muscle function and volume.Muscle function of sports-related amenorrhea.

Electrical stimulation prevents deterioration of the oxidative capacity of disuse-atrophied muscles in rats.

INTRODUCTION: The purpose of this study was to evaluate the effects of electrical stimulation on disuse-atrophied muscles. METHODS: Sprague-Dawley rats were used and divided into three groups: control (C), hind-limb suspended for 7 d (HS), and HS plus transcutaneous electrical stimulation for 7 d (ES). In the ES group, transcutaneous electrical stimulation was induced at 1 Hz for 1 h every day to condition the gastrocnemius-plantaris-soleus muscles. Muscle oxidative capacity was evaluated by 31P-MRS in vivo. Maximum tension and muscle wet mass were also measured. RESULTS: Muscle oxidative capacity decreased within 1 wk in HS; however, it was maintained when electric stimulation was applied to the suspended limb. The maximum twitch tension in HS was significantly smaller than that in C (p < 0.05), while in ES it did not differ from that in C. The muscle mass was significantly smaller in the HS and ES groups compared to C (p < 0.05). CONCLUSION: These data indicated that twitch electrical stimulation was effective in preventing deterioration of muscle functions, such as maximum tension and oxidative capacity, induced by 1 wk of disuse.

Pharmacological profile of AS-9705, a novel benzotriazolecarboxamide derivative, as a gastroprokinetic agent with potent anti-emetic activity.

The pharmacological profile of AS-9705 ((R)-N-(1-ethyl-1H-hexahydroazepin-3- yl)-6- methoxy-1H-benzotriazole-5-carboxamide fumarate monohydrate, CAS 219622-61-4), a novel gastroprokinetic agent with potent anti-emetic activity, was investigated in the present study. AS-9705 inhibited [3H]spiperone binding to human dopamine D2.long receptors, and [3H]R(+)-7-OH-DPAT binding to human dopamine D3 receptors (IC50 values of 58.5 +/- 14.0 and 60.8 +/- 7.8 (nmol/l), respectively) and had negligible affinity (IC50 > 10 mumol/l) for other neurotransmitter recognition sites examined. Moreover, in ferrets or dogs, AS-9705 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT and apomorphine with ID50 values of 0.05 mg/kg p.o. and 0.04 mg/kg p.o., respectively. AS-9705 dose-dependently enhanced normal gastric emptying and potently inhibited the delay in gastric empting induced by apomorphine, morphine, cisplatin, clonidine and cholecystokinin in rats. Furthermore, in conscious fasting dogs, AS-9705 dose-dependently stimulated gastric motility. In conclusion, AS-9705 is a novel gastroprokinetic agent with potent antiemetic activity and minimal CNS adverse effects and is, therefore, worthy of clinical investigation.

Novel and potent human and rat beta3-adrenergic receptor agonists containing substituted 3-indolylalkylamines.

A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human beta(3)-AR. The optically active 30a was found to be the most potent and selective human beta(3)-AR agonist in this series with an EC(50) value of 0.062nM. In addition, 30a selectivity for human beta(3)-AR was 210-fold and 103-fold that for human beta(2)-AR and beta(1)-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat beta(3)-AR.

Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.

A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.

Effects of mosapride citrate, a 5-HT4 receptor agonist, on colonic motility in conscious guinea pigs.

It is known that 5-HT(4) receptors in the colon of guinea pigs show a distribution similar to that in humans. Thus, we examined the effects of mosapride citrate (mosapride) and cisapride, two 5-HT(4)-receptor agonists, on colonic motility in conscious guinea pigs implanted with force transducers. Mosapride and cisapride administered intragastrically at doses of 3 - 30 mg/kg significantly enhanced the colonic motility. The enhancing effect of mosapride was antagonized by atropine or GR113808, a 5-HT(4)-receptor antagonist, but not by methysergide, a 5-HT(1)- and 5-HT(2)-receptor antagonist; ondansetron, a 5-HT(3)-receptor antagonist; or CP-99994, a tachykinin NK(1)-receptor antagonist. In vitro receptor autoradiography showed that mosapride and cisapride inhibit the specific binding of [(125)I]-SB207710, a selective radioligand of 5-HT(4) receptors, in the colon of guinea pigs. These results suggest that mosapride enhances colonic motility through the 5-HT(4)-receptor activation in guinea pigs and may be useful for treating constipation in patients with colonic motility dysfunction.

Effect of 6-hydroxydopamine treatment in the area postrema on morphine-induced emesis in ferrets.

To investigate the role of catecholamine release in emesis, we examined the effects of pretreatment with 6-hydroxydopamine (6-OH-DA) administered into the area postrema in morphine-induced emesis in ferrets. In the 6-OH-DA pre-treated animals, the latency to the first emetic response induced by morphine hydrochloride (1.0 mg/kg, s.c.) was significantly prolonged and the number of retches and emetic episodes was markedly reduced. In the medulla oblongata, the levels of dopamine and homovanilic acid were reduced by 6-OH-DA pretreatment. These results suggest that catecholamine release in the medulla oblongata, mainly dopamine release, may play an important role in morphine-induced emesis in ferrets.