EP3, but not EP2, FP, or TP prostanoid-receptor stimulation may reduce intraocular pressure.

Stimulation of DP, but not TP or FP, prostanoid receptors has previously been shown to reduce intraocular pressure (IOP) in rabbits. However the role of EP receptors (EP1, EP2, and EP3 subtypes) has not been studied extensively. Sulprostone, RS-61565, and RS-20216 have been studied for effects on rabbit IOP, and their prostanoid-receptor profiles characterized. The data suggest that the EP3, but not EP2, FP, or TP activity of these agonists correlated with the intraocular hypotensive effects. Moreover, RS-20216 lowered IOP at a dose of 5 micrograms for up to 12 hr after administration. In contrast to PGE1 and PGE2, which elicited both hyper- and hypotensive responses, sulprostone, RS-61565, and RS-20216 elicited only a hypotensive responses with no signs of ocular irritation. Thus stimulation of the EP3 receptor results in a lowering of IOP in rabbits. Compounds specific for this receptor subtype may act as novel therapeutic agents for the treatment of glaucoma.

Synthesis and pharmacological evaluation of N,N-di-n-propyldopamine congeners containing phenolic bioisosteres.

A series of analogues of N,N-di-n-propyldopamine (DPDA) in which the 3-hydroxyl group was replaced by bioisosteric groups was prepared and evaluated for D1- and D2-receptor affinity. The 3-methane-sulfonamide analogue (18) had a higher affinity for the D2 receptor than DPDA and was more selective for the D2 receptor. The 3-formamide derivative (15) also retained significant D2 affinity. Both of these compounds demonstrated in vivo cardiovascular and renal profiles in an anesthetized rat model that were consistent with selective D2-receptor agonism.

Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.

A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.

Stimulatory effect of enprostil, an anti-ulcer prostaglandin, on gastric mucus secretion.

Enprostil, a synthetic analogue of prostaglandin E2, is known to be a potent inhibitor of gastric acid secretion, and has marked anti-ulcer activity in rodents. Enprostil was administered in doses ranging from 15 to 250 micrograms/kg to rats prepared using the Shay procedure. Three hours later, the rats' stomachs were removed and processed either for the chemical determination of mucus, or for scanning electron microscopy. For the chemical determination, the secreted gastric juice was removed and the adherent gastric mucus was eluted with 2 M sodium chloride. The anthrone method was used to determine the mucus present. Enprostil was found to significantly increase gastric mucus at a dose of 60 micrograms/kg when measured by the anthrone test. Enprostil administered by the oral route was most effective in stimulating mucus secretion, suggesting a local or topical action of enprostil on mucus-secreting cells. Scanning electron microscopy of rat fundic mucosa after enprostil administration (50 to 100 micrograms/kg) revealed the presence of thin veil-like layers covering the epithelial surface, which was interpreted as an increase in mucus secretion. Higher magnifications (X 2,000) clearly showed the layers of mucus covering the surface epithelial cells. Enprostil's apparent increase of gastric mucus secretion may contribute to its anti-ulcer activity and may promote gastric healing.

Gastric mucosal binding studies with enprostil: a potent anti-ulcer prostaglandin.

The potent antiulcer prostaglandin enprostil binds with high affinity to porcine gastric mucosal tissues. This binding is saturable, dissociable and displaceable by compounds with similar structures. Various characteristics of binding such as pH optimum and displacement potencies suggest that enprostil binds to mucosal PGE2 sites. Structure-activity and gastric mucosal binding relationships were also examined.

Drug effects on the neovascularization response to silver nitrate cauterization of the rat cornea.

Neovascular growth into the cornea induced by silver nitrate cauterization is the basis of this experimental model developed to test potential anti-inflammatory drugs for ocular use. Cauterization of the rat cornea with a silver nitrate applicator stick provides the stimulus for neovascularization, which is scored by a "blinded" investigator. Burn stimulus intensity is also scored to substantiate a consistent stimulus among the groups. Compounds showing activity in this model include topical dexamethasone, prednisolone, ticabesone propionate, ketorolac, and phenidone. This model is presented as a practical method for testing anti-inflammatory drugs in the eye.

The effect of orally administered prostaglandins on gastric mucus secretion in the rat.

The secretion of gastric mucus may play a role in the protective effect of prostaglandins against gastric ulcers. To investigate the effect of prostaglandins E1, E2, F1alpha, F2alpha, A1, A2 and 15 (S) 15 methyl prostaglandin E2-methyl ester on gastric mucus secretion, these prostaglandins were given orally to rats at doses of 0.1, 1.0 and 4.0 mg/kg. The anthrone method was used to analyze the amount of mucus washed from the stomach with 2 M Nacl. Gastric secretory volume effects were also observed. All of the compounds tested increased both gastric mucus and secretory volume. The most active compound was 15(S)15 methyl PGE2 Me ester. The mucus stimulating effect of these prostaglandins, when administered locally, may be relevant to the understanding of the anti-ulcer effect of prostaglandins.

Synthesis and aldose reductase inhibitory activity of 7-sulfamoylxanthone-2-carboxylic acids.

A series of xanthone-2-carboxylic acids substituted in the 7 position with sulfamoyl and other groups was synthesized and assayed in vitro for inhibition of aldose reductase isolated from rabbit lenses. At a concentration of 10(-6) M, the N-methyl-N-(2-hydroxyethyl)sulfamoyl derivative 14 produced an 83% inhibition of aldose reductase. The structural requirements for this type of activity are discussed.

Drug effects on plasma renin activity in the mouse.

To investigate the possible effects of newly synthesized beta-adrenergic blockers on plasma renin activity, an assay was developed using unanesthetized mice and radioimmunoassay. Renin activity was significantly increased by the administration of hydralazine (1 mg/kg, i.p.), furosemide (20 mg/kg, i.v.), and isoproterenol (0.1 mg/kg, s.c.). Unlike isoproterenol, norepinephrine (1 mg/kg, s.c.) and epinephrine (1 mg/kg, s.c.) were active but considerably less effective stimulants. The increase caused by isoproterenol was blocked by clonidine, pindolol, bunolol, atenolol, and l-propranolol, but not d-propranolol. The beta-blockers with intrinsic sympathomimetic activity such as pindolol were found to increase renin activity when given alone, but blocked an increase in renin activity when given prior to isoproterenol. In general, nonselective beta-blocking drugs possessing both beta 1- and beta 2-(vascular) blocking activity were found to be most effective in blocking plasma renin activity on oral administration.