Combined tachykinin receptor antagonist: synthesis and stereochemical structure-activity relationships of novel morpholine analogues.

We report herein the synthesis and stereochemical structure-activity relationships of novel morpholine analogues 12 and 13 with regards to NK1, NK2 and NK3 tachykinin receptor binding affinity. An essential requirement for more potent binding affinities was controlled by absolute configuration. (S,R)-12 and (S,R)-13 exhibited high binding affinities for NK1, NK2 and NK3 receptors.

Combined NK1 and NK2 tachykinin receptor antagonists: synthesis and structure-activity relationships of novel oxazolidine analogues.

We report herein the synthesis and structure-activity relationships of a series of novel oxazolidine analogues with regards to NK1 and NK2 tachykinin receptor binding affinity. Among this series of oxazolidine analogues, some compounds exhibited excellent high binding affinities for both NK1 and NK2 receptors. In addition, we describe the inhibitory effect in vivo on SP-induced airway vascular hyperpermeability and NKA-induced bronchoconstriction in guinea pigs.

Effects of a thromboxane synthase inhibitor (CS-518) on the eosinophil-dependent late asthmatic response and airway hyperresponsiveness in guinea pigs.

The effects of CS-518, a thromboxane A2 synthase inhibitor, on antigen-induced dual bronchial responses, airway hyperresponsiveness (AHR) and airway eosinophilia were investigated in an experimental guinea pig model of the late asthmatic response. Oral CS-518 (1 and 10 mg/kg) inhibited immediate and late asthmatic responses dose-dependently. It also inhibited AHR and eosinophil accumulation after antigen challenge. Therefore, thromboxane A2 is possibly involved in development of the late asthmatic response and AHR, and CS-518 was inferred to inhibit these via inhibition of eosinophil accumulation and thromboxane production.

Relationship between airway eosinophilia and airway hyperresponsiveness in a late asthmatic model of guinea pigs.

To elucidate the mechanism of development of asthma, we tried to develop a model which elicited a late asthmatic response by a combination of systemic and inhaled sensitization with ovalbumin in guinea pigs. Eighty-seven percent of animals elicited both an immediate and late asthmatic response after the third antigen inhalation. Airway eosinophilia and airway hyperresponsiveness (AHR) induced after the third challenge were more severe than those after the first challenge. There was a good correlation between airway eosinophilia and AHR in this model under experimental modulation of the number of eosinophils, such as by interleukin 5 or antieosinophil antibody injection. These results demonstrate that eosinophils play an important role in the development of late asthmatic response and AHR.

Effects of CS-518, a thromboxane synthase inhibitor, on eosinophil function.

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a thromboxane A2 synthase inhibitor, on eosinophil accumulation and activation were investigated in an experimental asthmatic guinea pig model and several cellular models. In the in vivo studies, CS-518 inhibited the biphasic eosinophil accumulation in the bronchoalveolar lavage fluid, potently in the early phase, but less potently in the delayed phase. On the other hand, even at the lower dose, CS-518 completely inhibited the hypodensity of eosinophils in the delayed phase. In the in vitro studies, CS-518 suppressed thromboxane A2 production and potentiated prostaglandin I2 production from guinea pig eosinophils. Moreover, CS-518 and prostaglandin I2 suppressed chemotaxis, peroxidase release and superoxide generation in guinea pig eosinophils. In addition, the present studies provide further support for the possibility that thromboxane A2 and prostaglandin I2, which are produced in bronchoalveolar tissue and within eosinophils, are involved in modulation of eosinophil function and suggest that CS-518 is a potent inhibitor of eosinophil activation.

Alteration of eicosanoid production in the sensitized guinea pig lung by CS-518.

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo [b]thiophene-6-carboxylate), a thromboxane A2 synthase inhibitor, on changes in arachidonic acid metabolism were investigated in the lung of actively sensitized guinea pigs. Antigen challenge enhanced the production of thromboxane A2 as well as histamine and peptide leukotrienes in lung fragments. Exogenous leukotriene D4 also stimulated significant thromboxane A2 production in the non-sensitized lung in vitro. CS-518 was effective in preventing the thromboxane A2 production induced by either antigen or leukotriene D4, and the IC50 values were 90 and 7.5 ng/ml (320 and 27 nM), respectively. CS-518 markedly potentiated the production of prostaglandin E2 and I2 with slight inhibition of leukotriene formation, but indomethacin significantly stimulated leukotriene production. When CS-518 was administered orally, it induced long-lasting inhibition of thromboxane A2 production and potentiation of prostaglandin I2 production in guinea pig lung. Thus, CS-518 not only inhibited thromboxane production but also improved the change in arachidonic acid metabolism in the guinea pig bronchoalveolar tissue during allergic reaction in vivo as well as in vitro, which suggests amelioration of the asthmatic condition.

Effects of CS-518, a thromboxane synthase inhibitor, on the asthmatic response.

The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.

Effects of dopamine receptor and alpha 2-adrenoceptor agonists and antagonists on muscarinic receptor stimulation in cardiac sympathetic ganglia of the dog.

The effects of dopamine (DA)-receptor and alpha 2-adrenoceptor agonists and antagonists on ganglionic muscarinic stimulation were examined in anesthetized dogs. All drugs were injected or infused intra-arterially into the blood supply of the cardiac sympathetic ganglia. The muscarinic agonists McN-A-343 (10, 20, and 30 micrograms) and muscarine (1, 2, and 3 micrograms) increased heart rate. The muscarinic receptor stimulation elicited by McN-A-343 or muscarine was significantly inhibited by infusion of the DA2-receptor agonist quinpirole (3 and 10 micrograms/min) but not by the DA1-receptor agonist SK&F 38393 (10 and 30 micrograms/min). The alpha 2-adrenoceptor agonist BHT 933 (3 and 10 micrograms/min) also inhibited muscarinic receptor stimulation. The DA2-receptor antagonist domperidone (10 micrograms/min) and the alpha 2-adrenoceptor antagonist yohimbine (1 micrograms/min) had no effects on muscarinic receptor stimulation, but they antagonized the inhibitory effects of quinpirole and BHT 933, respectively. The nicotinic transmission elicited by preganglionic cardiac sympathetic nerve stimulation (1 and 2 Hz) was also inhibited by DA-receptor and alpha 2-adrenoceptor agonists and antagonists. These results suggest that DA2-receptors and alpha 2-adrenoceptors suppress muscarinic transmission as well as nicotinic transmission in the cardiac sympathetic ganglia of the dog.

Effects of pirenzepine and AF-DX 116 on ganglionic transmission in the cardiac sympathetic nerves of the dog: interaction of M1 and M2 receptors with nicotinic receptors.

Effects of the selective M1 receptor antagonist pirenzepine and the selective M2 receptor antagonist AF-DX 116 on ganglionic transmission were examined in anesthetized dogs, in order to elucidate a functional role of M1 and M2 receptors. Preganglionic or postganglionic stimulation of the cardiac sympathetic nerves (SNS, 0.5-16 Hz) produced frequency-dependent increases in heart rate. Pirenzepine (3-100 microgram/kg) caused dose-dependent and significant inhibition of positive chronotropic response to preganglionic SNS but not to postganglionic SNS. AF-DX 116 (10-100 micrograms/kg) had no effect on the preganglionic SNS-induced tachycardia. The simultaneous administration of pirenzepine (30 micrograms/kg) and hexamethonium (C6, 1 mg/kg), and the subsequent administration of 10 mg/kg of C6, inhibited more potently the tachycardic responses to preganglionic SNS than each dose of C6 did by itself. The enhancement by pirenzepine of the C6-induced inhibition was evident at high frequencies (8 and 16 Hz) of SNS. In contrast, the blocking effect of C6 (1 and 10 mg/kg) on ganglionic transmission was significantly attenuated by AF-DX 116 (30 micrograms/kg). The attenuation by AF-DX 116 was observed at a wide range of stimulation frequency (0.5-8 Hz). These results suggest that M1 receptors play a facilitatory role in ganglionic transmission but M2 receptors do not contribute to the transmission when nicotinic pathway is intact. However, the activation of M2 receptors would further suppress ganglionic transmission when nicotinic transmission is inhibited. Under these conditions, activation of M1 receptors would mediate the transmission elicited by high frequency of stimulation.

Inhibitory effects of diltiazem, verapamil, nifedipine, and nicardipine on sympathetic tachycardia in decentralized hearts of anesthetized dogs.

Intravenous diltiazem (10-300 micrograms/kg), verapamil (10-300 micrograms/kg), nifedipine (1-100 micrograms/kg) and nicardipine (1-100 micrograms/kg) inhibited the tachycardia caused by cardiac sympathetic nerve stimulation (SNS, 0.5-4 Hz) in decentralized hearts of anesthetized dogs. The dose range of each drug required to inhibit the SNS-induced tachycardia was almost equivalent to that required to produce the increase in coronary blood flow and the decrease in blood pressure. Nifedipine and nicardipine were equi-active and about 10 times more potent than diltiazem and verapamil in inhibiting the SNS-induced tachycardia. They produced a slight but dose-dependent slowing of the resting heart rate. The negative chronotropic potency was approximately nicardipine, verapamil greater than nifedipine, diltiazem. Bay K 8644 (30 micrograms/kg) antagonized the inhibitory effects of diltiazem (100 micrograms/kg) and nifedipine (30 micrograms/kg) on the SNS-induced tachycardia. Tachycardia induced by intracoronary norepinephrine (0.03-0.3 micrograms) was suppressed by diltiazem (30-300 micrograms/kg) and nifedipine (10-100 micrograms/kg). The inhibitory effects of calcium entry blocking drugs on the sympathetic tachycardia appear to be explained by the interference of the beta-adrenoceptor-mediated increase in slow inward current in the sinoatrial (SA) node. It is also suggested that other mechanisms different from calcium entry blocking action contribute to the negative chronotropic response to these calcium entry blocking drugs.