Anti-obesity and anti-diabetic activities of a new beta3 adrenergic receptor agonist, (S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl] phenoxy] acetic acid ethanedioic acid (SWR-0342SA), in KK-Ay mice.

We investigated the beta-adrenergic receptor (AR) agonistic activities in rats and humans, and the anti-obesity and anti-diabetic activities in KK-Ay mice, of a new beta3-AR agonist, SWR-0342SA ((S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-pro penyl]phenoxy] acetic acid ethanedioic acid). With regards to its beta-AR agonistic activity in rats, SWR-0342SA stimulated the atrial beating rate (beta1-AR activity) and white adipocyte lipolysis (beta3-AR activity), but did not induce uterine muscle relaxation (beta2-AR activity). The beta3-AR agonistic activity of SWR-0342SA was about 20 times stronger than its beta1-AR agonistic activity. Similarly, SWR-0342SA enhanced the accumulation of cAMP in Chinese hamster ovary (CHO) cells expressing human beta1- and beta3-ARs, while having no effect in CHO cells expressing beta2-ARs. Adenylyl cyclase stimulation by SWR-0342SA in CHO cells expressing beta3-ARs was about 35 times higher than that in CHO cells expressing beta1-ARs. With regards to anti-obesity and anti-diabetic activities, SWR-0342SA had no effect on body weight or food intake, but slightly decreased the fat pads weight in KK-Ay mice, an animal model of obesity and non-insulin-dependent diabetes mellitus (NIDDM). On the other hand, SWR-0342SA significantly decreased both blood glucose (to about 46% of control) and serum insulin levels (to about 40% of control) in KK-Ay mice. These results indicated that SWR-0342SA is a selective beta3-AR agonist, and possesses potent anti-diabetic activity, and that the anti-obesity activity is inferior to the anti-diabetic activity.

Pharmacological profiles of a new antiulcer agent, SWR-215.

We investigated the effects of a new antiulcer agent, SWR-215 ([[(1,2-dihydro-2-oxo-4-quinolinyl)methyl]thio]-N-[[[4-(1-piperidinyl methyl)-2-pyridinyl]oxy]-Z-2-butenyl]acetamide), on histamine H2-receptors, gastric acid secretion and various acute experimental gastric lesions. SWR-215 showed unsurmountable histamine H2-antagonism on isolated guinea-pig atrium. In gastric secretion studies, SWR-215 exhibited potent and durable inhibitory effects, and the antisecretory activities were much stronger than that of roxatidine acetate hydrochloride (roxatidine): 5 times stronger on basal acid secretion in pylorus ligated rats, 11 times stronger on histamine-stimulated acid secretion in acute fistula rats, and 2 times stronger on histamine stimulated acid secretion in Heidenhain-pouch dogs, respectively. In various experimental acute gastric lesion studies, SWR-215 potentially inhibited almost all acute gastric and duodenal lesions compared with roxatidine, especially indomethacin-induced and HCl-ethanol-induced gastric lesions, and the inhibitory effects were exhibited at the same or lower doses than those which caused the antisecretory effect. Furthermore, it was considered that the mucosal protective effect of SWR-215 was probably unrelated to the endogenous prostaglandin system in gastric mucosa. These results suggest that SWR-215 possesses both durable antisecretory and mucosal protective effects, and is expected to be a useful drug for the treatment of patients with peptic ulcers.

[Effects of Cuban analog (SWR-104SA), a new histamine H2 receptor antagonist, on gastric acid secretion and experimental ulcer formation].

The antagonism of histamine H2-receptor by SWR-104SA (1'-bromo-N-[3-[3-(1-piperidinylmethyl) phenoxy] propyl]-spiro [1,3-dioxolane-2,9'-pentacyclo-[4.3.0.0.(2,5)0.(3,8) 0.(4,7)]nonane]-4'-carboxamide monooxalate) was estimated using the isolated guinea-pig atrium and gastric acid secretion in rats. The concentration-response curves for the positive chronotropic effect of histamine on the atrium were displaced to the right in parallel without change in the maximum response by SWR-104SA and roxatidine acetate hydrochloride (roxatidine). The pA2 values of SWA-104SA and roxatidine acetate hydrochloride were 7.27 and 7.38, respectively. The slopes of the regression line of log (DR-1) against log SWR-104SA and roxatidine concentration were 1.00 and 0.92, respectively. There was no significant difference between the two compounds with respect to the histamine H2-receptor antagonism and/or binding manner in vitro. In the rat gastric fistula model stimulated by histamine, however, antisecretory potency of SWR-104SA was 3 times less than that of roxatidine. SWR-104SA given p.o. prevented the formation of gastric lesion induced by HCl-ethanol and indomethacin dose-dependently, roxatidine also prevented its formation by HCl-ethanol, but failed to prevent that by indomethacine. These antiulcer activities of SWR-104SA were shown at the lesser doses of antisecretory activity. On the other hand, roxatidine did not prevent the ulcer formation at the same dose level of antisecretory activity. These results indicate that the antiulcer effect of SWR-104SA is not caused by the antisecretory action alone. In addition, the mucosal protective activity of SWR-104SA for HCl-ethanol induced gastric lesion was independent of endogenous prostaglandins. Moreover SWR-104SA had inhibitory effects on indomethacin-induced gastric hypermotility in rats. These actions may partly explain the gastric protection of this compound and additional mechanisms such as mucosal blood flow could be involved in the antiulcer efficacy. Consequently, it appears that SWR-104SA is a new antiulcer drug that exerts a potent cytoprotective effect in addition to its gastric antisecretory activity.

Granuloma-forming activity and antitumor activity of newly isolated mycoloyl glycolipid from Rhodococcus terrae 70012 (Rt. GM-2).

A newly isolated mycoloyl glycolipid (Rt. GM-2) from Rhodococcus terrae 70012 was identified and the granulomagenic and antitumor activities were studied as compared with trehalose-6,6'-dimycolate (cord factor) also from R. terrae (Rt. TDM). The alkaline hydrolysis products of Rt. GM-2 contained trehalose, methyl-alpha-mycolate and a less-polar ester than the usual methyl-alpha-mycolate, possibly beta-keto mycolate (1:1:1, by mol. ratios). On the other hand, analysis of alditol acetate obtained after the mild permethylation, NaBH4 reduction, and acetylation showed the occurrence of 2,3,4-tri-O-methyl-6-O-acetylglucitol. Therefore, the original glycolipid (Rt. GM-2) was identified tentatively as 6-O-alpha-mycoloyl 6'-O-beta-ketomycoloyl trehalose. Intravenous injection of Rt. GM-2 in the form of water-in-oil-in-water emulsion caused prominent granulomas in lungs and spleen of ICR and BALB/c mice. The granulomagenic effects were as strong as those caused by Rt. TDM. The lung and spleen weights reached peaks one week after an injection of Rt. GM-2 in mice and then gradually decreased. Multiple intravenous injections of Rt. GM-2 and Rt. TDM showed antitumor activity against subcutaneously implanted Sarcoma-180, and caused prominent granulomatous changes and growth suppression of mice.