2,4-Disubstituted oxazoles and thiazoles as latent pharmacophores for diacylhydrazine of SC-51089, a potent PGE2 antagonist.

8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (1, SC-51089) is a functional PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activity. Analogues of SC-51089, in which the diacylhydrazine moiety has been replaced with 2,4-disubstituted-oxazoles and-thiazoles, are described.

Aminoacetyl moiety as a potential surrogate for diacylhydrazine group of SC-51089, a potent PGE2 antagonist, and its analogs.

8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (1, SC-51089) is a functional PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activity. During metabolism in cultured rat hepatocytes, SC-51089, which contains a diacylhydrazine moiety, has been shown to release hydrazine. Analogs of SC-51089, in which the diacylhydrazine functionality has been replaced by isosteric and isoelectronic groups, have been synthesized and have been shown to be analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure-activity relationships within these series.

Enkephalin analogs as systemically active antinociceptive agents: O- and N-alkylated derivatives of the dipeptide amide L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide.

A number of O- and N-alkylated derivatives of the antinociceptive, orally active, mu-opioid-selective truncated enkephalin analog L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide (2, SC-39566) were synthesized to explore the structure-activity relationships of the series. The parent molecule is quite forgiving of substitution on the tyrosyl phenolic moiety and on the alanyl nitrogen. The tyrosyl and (phenylpropyl)amide NH sites, however, appear to be critical to interactions with the receptor, for even modest changes at these sites cause great loss of binding potency.

N-substituted dibenzoxazepines as analgesic PGE2 antagonists.

8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide (1, SC-19220) has been previously reported by us and others to be a PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activities. Analogs of SC-19220, in which the acetyl moiety has been replaced with pyridylpropionyl groups and their homologs, have been synthesized as illustrated by compounds 13 and 29. These and other members of this series have been shown to be efficacious analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure activity relationships within this series.

Muscarine stimulates the hydrolysis of inositol-containing phospholipids in the superior cervical ganglion.

Previous studies have shown that muscarine increases the incorporation of 32Pi and [3H]inositol into phosphatidylinositol in the superior cervical ganglion of the rat. Because the first event in agonist-stimulated phospholipid turnover is thought to be the hydrolysis of phosphatidylinositol or of phosphatidylinositol phosphates, we measured the accumulation of [3H]inositol phosphates in ganglia in which these lipids had been labeled by preincubation with [3H]inositol. The production of [3H]inositol phosphates under these conditions presumably reflects the activity of a phospholipase C in the ganglion. Muscarine caused a large increase in the formation of [3H]inositol phosphates. Most of this increase was in the form of [3H]inositol-1-phosphate. The stimulation of [3H]inositol phosphate accumulation by muscarine was not dependent upon the presence of extracellular Ca++. Agents that increase Ca++ influx caused only a small increase in the accumulation of [3H]inositol phosphates. We also measured the formation of [3H]inositol phosphates in extracts of the ganglion. These extracts contained a phospholipase C activity that was stimulated by deoxycholate and that hydrolyzed phosphatidylinositol phosphates more actively than phosphatidylinositol. This phospholipase C activity was Ca++-dependent. We propose that muscarine may activate this phospholipase C in the intact ganglion and that muscarine increases phospholipase C activity by some mechanism other than by increasing the influx of Ca++.

Effects of neuronal activity on inositol phospholipid metabolism in the rat autonomic nervous system.

The effect of nerve stimulation on inositol phospholipid hydrolysis in autonomic tissue was assessed by direct measurement of [3H]inositol phosphate production in ganglia that had been preincubated with [3H]inositol. Within minutes, stimulation of the preganglionic nerve increased the [3H]inositol phosphate content of the superior cervical sympathetic ganglion indicating increased hydrolysis of inositol phospholipids. This effect was blocked in a low Ca2+, high Mg2+ medium. It was also greatly reduced when nicotinic and muscarinic antagonists were present together in normal medium. However, neither the nicotinic antagonist nor the muscarinic antagonist alone appeared to be as effective as both in combination. In other experiments, stimulation of the vagus nerve caused dramatic increases in [3H]inositol phosphate in the nodose ganglion but did not increase [3H]inositol phosphate in the nerve itself. This effect was insensitive to the cholinergic antagonists. Thus, neuronal activity increased inositol phospholipid hydrolysis in a sympathetic ganglion rich in synapses, as well as in a sensory ganglion that contains few synapses. In the sympathetic ganglion, synaptic stimulation activated inositol phospholipid hydrolysis and this was primarily due to cholinergic transmission; both nicotinic and muscarinic pathways appeared to be involved.

Muscarine increases tyrosine 3-monooxygenase activity and phospholipid metabolism in the superior cervical ganglion of the rat.

Muscarinic agonists cause a stable activation of tyrosine 3-monooxygenase in the superior cervical ganglion and increase the incorporation of 32Pi into phospholipids in the ganglion. We have studied the relationship between muscarine-stimulated phospholipid turnover and the muscarine-induced activation of tyrosine 3-monooxygenase. Both effects of muscarine are apparent within 2 min of incubation, and both are essentially independent of extracellular Ca++. All concentrations of muscarine that increase dopa synthesis also stimulate phospholipid turnover. Bethanechol is less efficacious than muscarine in producing both of these effects. Lithium, which disrupts phospholipid metabolism, inhibits the muscarine-stimulated accumulation of dopa. Other agents which affect phospholipid metabolism, including phospholipase C and deoxycholate, also increase the synthesis of dopa in the ganglion. These data support the hypothesis that changes in phospholipid metabolism mediate the activation of tyrosine 3-monooxygenase by muscarinic agonists.