Antagonism of prostaglandin-induced cyclic AMP accumulation in the rat anterior pituitary in vitro by somatostatin analogues.

The PGE2-induced cyclic AMP accumulation in the rat anterior pituitary in vitro is inhibited by [desamino1]-[desamino1] [descarboxy14]- and [D-Lys4]-somatostatin similarly to somatostatin, while the [descarboxy14]-somatostatin exhibits reduced activity; [D-Lys9]-somatostatin is ineffective at a higher concentration.     

On the synthesis of serine and homoserine samples asymmetrically labelled with tritium and deuterium in the hydroxymethylene group.

(1R) [1-3H, 2H1] 3-Phenylpropanol, the key intermediate in the synthesis of (4R) [4-3H, 2H1] D,L-homoserine and of the (4S)-isomer, is obtained from (1S) [1-2H1] 3-phenylpropanol and (1RS) [1-3H] ethanol upon incubation with yeast alcohol dehydrogenase and NAD+; under similar conditions 2-phenylethanol undergoes very small exchange with [1-2H2] ethanol.     

Reaction of resorcinol with isoprene

Zusammenfassung Die Synthese von 7-Hydroxy-2, 2-dimethylchroman, 6,7-Dihydro-2,2,8,8-tetramethyl-8H-[1]pyrano[3,2-g]chroman und 9,10-Dihydro-2,2,8,8-tetramethyl-8H-[1]pyrano[2,3-h]chroman aus Resorcin und Isopren oder 1-Bromo-3-methyl-2-buten wird beschrieben.     

Invertebrate neuropeptides resembling vasotocin and some analogues: synthesis and pharmacological properties

The solid phase synthesis of three invertebrate vasopressin-oxytocin homologs: AVP-like factor, F1(1), ([Leu2, Thr4] AVT)2 isolated from subesophageal and thoracic ganglia of Locusta migratoria3, Arg-conopressin-S4. ([Ile2, Arg4] AVT), Lys-conopressin-G4 ([Phe2, Arg4] LVT), both isolated from the venom of fish-hunting marine snails of the genus Conus and six of their analogues is reported. These analogues are: [Arg4] AVT, [Ile2] AVT, [Leu2] AVT, [Phe2, Arg4] AVT, [Arg4] LVT and [Ile2, Arg4] LVT. All peptides were tested for antidiuretic and vasopressor activities.     

Dérivés trifluorométhylés des [1]benzothiopyrano[4,3-b]indoles et des 6H-[1]benzothiopyrano-[4,3-b]quinoléines

Summary Some fluoro derivatives of [1]benzothiopyrano[4,3-b]indoles and 6H[1]benzothiopyrano[4,3-b] quinolines have shown carciuogenic activities in regard to the fluorine position; we thought it interesting to prepare some trifluoromethyl analogs of there compounds to study the biological activities and to compare with other compounds of the same family. In the present work, we report the synthesis of 7-trifluoromethyl and 8-trifluoromethyl [1]thiochroman-4-one and some [1]benzothiopyrano[4,3-b]indoles and quinolines substitued in 3 or 4 position which have been obtained from these two ketones.     

Visually guided movement in the cat: difference in the effects of a bilateral lesion of the thalamic nucleus ventralis lateralis performed either before or after training]

Bilatéral lesions of the thalamic nucleus ventralis lateralis were performed in cats, either after [1] or before [2] training to reach a moving target with the forepaw. In situation [1], lesions were ineffective; in situation [2] the animal never reached normal scores. VL thus seems to be essential only in the acquisition phase of the tested visuomotor performance.     

3[H]-Sulpiride labels mesolimbic non-dopaminergic sites that bind antidepressant drugs

3[H]-(-)-Sulpiride and 3[H]-spiperone binding was compared in rat amygdala, nucleus accumbens and striatum, using (+/-)-sulpiride to define specific binding. 3[H]-(-)-Sulpiride bound to twice as many sites in amygdala and nucleus accumbens as 3[H]-spiperone. 3[H]-(-)-Sulpiride binding was directed to these additional sites by using 1 microM spiperone to mask dopaminergic binding. The binding of 3[H]-(-)-sulpiride to these sites was high affinity, reversible, Na+-dependent, but not stereospecific. Metoclopramide, tiapride and antidepressant medications, but not other neuroleptics, ADTN, or serotonin displaced 3[H]-(-)-sulpiride binding to these sites. These data suggest that 3[H]-(-)-sulpiride labels mesolimbic sites other than dopamine receptors which may mediate antidepressant effects.     

Serotonin-stimulated protein phosphorylation in aortic smooth muscle cells

The effects of serotonin on the formation of inositol phosphates and protein phosphorylation were examined in cultured smooth muscle cells. Serotonin stimulated the formation of [3H]inositol monophosphate, [3H]inositol bisphosphate and [3H]inositol trisphosphate. This effect was prevented by 5-HT2 specific antagonist, 6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid, 2-hydroxy-1-methylpropyl ester [Z]-2-butenedioate (LY53857). Serotonin stimulated the phosphorylation of many polypeptides, among which a 20 kDa polypeptide was the most prominent. The phosphorylation was also inhibited by LY53857. LY53857 alone produced no effects on protein phosphorylation. The 20 kDa polypeptides were also phosphorylated by the addition of 12-O-tetradecanoylphorbol-13-acetate. These results suggest that serotonin stimulates protein phosphorylation through 5-HT2 receptors and possibly activates protein kinase C in intact vascular smooth muscle cells.     

Synthesis and pharmacological properties of [1-N4-dimethyl-asparagine]-angiotensin II.

[1-N4-Dimethyl-asparagine]-angiotensin II was synthesized by Merrifield's solid-phase procedure. The analogue gave rat blood pressure about 70% relative potency to Hypertension (Ciba). Rabbit aorta strips gave intrinsic activity alpha E = 1, a PD2 of 6.92 +/- 0.09 and an affinity relative to [Asn1]-angiotensin II of 6.5%.     

Opioids and cytosolic calcium in rat anterior pituitary: dynorphin preparation showed LHRH-like action due to contamination

The effect of dynorphin A-(1-13) (Dyn A-(1-13] and other opioids on the cytosolic free calcium concentration [(Ca2+]i) in rat anterior pituitary cells was examined using the fluorescent indicator fura-2. A commercial synthetic Dyn A-(1-13) preparation elevated [Ca2+]i. Results, which were obtained with receptor antagonists, and in LHRH receptor radioligand binding studies as well as by HPLC combined with LHRH radioimmunoassay, strongly suggest that this effect of the dynorphin preparation was due to contamination with a LHRH-like compound. Dyn A-(1-13), purified by HPLC, as well as Dyn A-(2-13), [Leu5]enkephalin, beta-endorphin, morphine, or U50,488H had no effect on [Ca2+]i. LHRH caused a rapid increase in [Ca2+]i by about 50 nM which was blocked by the LHRH antagonist, [D-pGlu1,D-Phe2,D-Trp3,6] LHRH.     

On 5-hydroxybenzo[b]naphtho[2,1-d]furan

Zusammenfassung Für die früher als 5-Hydroxybenzo [b]naphto[2, 1-d]furan beschriebene Verbindung wird die Struktur II vorgeschlagen und eine Synthese des ersteren (III) beschrieben.     

Inhibition of alpha-chymotrypsin by 2-halogeno-ethanols; comparisons with 2-methyl-ethanols and urea.

2-Halogeno- and 2-methyl-ethanols inhibit alpha-chymotrypsin in the order of their substituted groups: [1] tri- greater than di- greater than mono-, [2] Br- greater than Cl- greater than CH3- greater than F-. The inhibition by the halogeno-ethanols is mediated differently from that by the methyl-ethanols, ethanol, and urea.     

Insect tissues, not microorganisms, produce linoleic acid in the house cricket and the American cockroach

Biosynthesis of linoleic acid, 18:2 (n-6), was unambiguously demonstrated to occur in the cockroach, Periplaneta americana, and the cricket, Acheta domesticus. Axenic tissue from both of these insect species was demonstrated by radio-gas-liquid chromatography (radio-GLC) and radio-high-performance liquid chromatography (radio-HPLC) to incorporate [1-14C]acetate and [1-14C]oleate into this essential fatty acid.     

On the synthesis of serine and homoserine samples asymmetrically labelled with tritium and deuterium in the hydroxymethylene group

Summary (1 R) [1-³H,²H₁] 3-Phenylpropanol, the key intermediate in the synthesis of (4 R) [4-³H,²H₁] D, L-homoserine and of the (4 S)-isomer, is obtained from (1 S) [1-²H₁] 3-phenylpropanol and (1 RS) [1-³H] ethanol upon incubation with yeast alcohol dehydrogenase and NAD⁺; under similar conditions 2-phenylethanol undergoes very small exchange with [1-²H₂] ethanol.     

Serotonin-stimulated protein phosphorylation in aortic smooth muscle cells

Summary The effects of serotonin on the formation of inositol phosphates and protein phosphorylation were examined in cultured smooth muscle cells. Serotonin stimulated the formation of [³H]inositol monophosphate, [³H]inositol bisphosphate and [³H]inositol trisphosphate. This effect was prevented by 5-HT₂ specific antagonist, 6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid, 2-hydroxy-1-methylpropyl ester [Z]-2-butenedioate (LY53857). Serotonin stimulated the phosphorylation of many polypeptides, among which a 20 kDa polypeptide was the most prominent. The phosphorylation was also inhibited by LY53857. LY53857 alone produced no effects on protein phosphorylation. The 20 kDa polypeptides were also phosphorylated by the addition of 12-O-tetradecanoylphorbol-13-acetate. These results suggest that serotonin stimulates protein phosphorylation through 5-HT₂ receptors and possibly activates protein kinase C in intact vascular smooth muscle cells.Part of the data contained in this paper was presented at the 74th local meeting of the Japanese Society of Pharmacology at Kanagawa.     

Studies on the serotonin transporter in platelets

[3H]-Imipramine and [3H]-paroxetine label with high affinity a recognition site which is associated with the serotonergic transporter in blood platelets. The pharmacological profile of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of drugs to inhibit the uptake of serotonin. Dissociation kinetic experiments suggest that the substrate recognition site for serotonin may be different from the modulatory site which is labeled with [3H]-imipramine or [3H]-paroxetine. The existence of an endocoid acting on the imipramine receptor to modulate the serotonin transporter has been proposed by several laboratories. In clinical studies most laboratories have reported a decrease in Bmax of [3H]-imipramine binding in platelets from depressed untreated patients when compared with matched healthy volunteers. The Bmax of [3H]-imipramine binding in platelets appears to be a state-dependent biological marker in depression.     

Metabolism of 1,3,7-trimethyldihydrouric acid in the rat: New metabolic pathway of caffeine

Summary [1-CH₃-¹⁴C] 1,3,7-trimethyldihydrouric acid which, in quantity, is the most important caffeine metabolite, was isolated and purified from the urine of rats fed with [1-CH₃-¹⁴C] caffeine. The oral administration of this metabolite to rats showed that 1,3,7-trimethyldihydrouric acid was excreted unchanged in urine and was therefore an end product of caffeine metabolism. This result implies a new metabolic pathway of caffeine.     

Serum-induced stimulation of snRNA synthesis in mouse 3T3 fibroblasts

Small nuclear RNAs (snRNAs) from quiescent and serum-stimulated 3T3 cultures, labeled with [3H]uridine [( 3H]U), were electrophoresed in polyacrylamide-urea slab gels and revealed by staining with ethidium bromide and by fluorography. Judged by labeling with [3H]U, synthesis of 7S and U1-U6 RNAs was very low or absent in quiescent cultures. The serum-induced transition of 3T3 cells from a resting to a growing state was accompanied by an early, apparently sequential stimulation of snRNA synthesis; stimulated synthesis of 7S, U1, U2, U3, U4 and U6 RNAs coincided in time with serum-induced stimulation of 45S pre-ribosomal RNA (pre-rRNA) and heterogeneous nuclear RNA (hnRNA) synthesis.     

Inhibition ofα-chymotrypsin by 2-halogeno-ethanols; comparison with 2-methyl-ethanols and urea

Summary 2-Halogeno- and 2-methyl-ethanols inhibit-chymotrypsin in the order of their substituted groups: [1] tri>di->mono-, [2] Br->Cl->CH₃->F-. The inhibition by the halogeno-ethanols is mediated differently from that by the methyl-ethanols, ethanol, and urea.     

The role of glycine in the biosynthesis of steroids

Zusammenfassung Während der Biosynthese von Cholesterol mit homogenisierter Rattenleber wird [2-¹⁴C] des Glycins viel besser eingebaut als [1-¹⁴C].Saccharomyces cerevisiae produziert radioaktives Squelen (ausser Ergosterol mit Radioaktivität des Ringsystems) mit [2-¹⁴C] Glycin und mit [3-¹⁴C] Serin, aber nicht mit [1-¹⁴C] Glycin.

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Studies on Biosynthesis. Part VI. For Part V, seeA. K. Bose, K. S. Khanchandani andB. L. Hungund, Experientia,27, 1403 (1971). b) Presented at the 164th National Meeting of the American Chemical Society, New York, August, 1972.

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The support of this research by Stevens Institute of Technology and Sandoz Foundation is gratefully acknowledged. We wish to thank Drs.P. T. Funke, M. S. Manhas, P. K. Bhattacharyya, M. Anchel andH. Levey for valuable discussions and help with some of the experiments.