Oxidation of synephrine by type A and type B monoamine oxidase

Summary Synephrine (SP) was found to be a substrate for monoamine oxidase (MAO) in rat brain mitochondria, showing the K_m and V_max values of 250 M and 32.6 nmoles/mg of protein/30 min respectively. The inhibition studies showed that the SP oxidation was carried out by both type A and type B MAO and a major part of the activity was due to type A MAO.     

Distribution of type A and B monoamine oxidase activities in the central nervous system of rat and chick

Summary The distribution of type A and B monoamine oxidase (MAO) activities in the central nervous system (CNS) of rat and chick was investigated using 5-hydroxytryptamine and -phenylethylamine as specific substrates. The distribution of type A MAO was similar to that of type B MAO in rat CNS, but quite different in chick CNS. This may be ascribed to the difference in animal species. The major part of MAO activity in the spinal cord was found to be type A.     

Multiplicity of monoamine oxidase in chick brain

Summary The substrate- and inhibitor-related characteristics of monoamine oxidase (MAO) were studied on chick brain mitochondria. It was found that neither 5-hydroxytryptamine nor -phenylethylamine is the specific substrate for type A and type B MAO in chick brain.     

Effect of adrenalectomy and dexamethasone treatment on the monoamine oxidase activity in the thyroid gland of the rat

Summary Adrenalectomy increased MAO activity in the thyroid gland of rats. The administration (200 g/100 g daily for 7 days) to adrenalectomized rats decreased MAO activity below levels of intact controls.     

Activité de la monoamine-oxydase au cours de la période perí-natale chez le Lapin

Summary The activity of enzyme monoamine oxidase was studied from 3 days before birth up to 2 days after birth in the heart, liver and kidney of albino rabbits. At the end of ftal life, the MAO activity of heart and liver expressed per unit of organ weight was nearly the same as the adult one. At birth and 1 day, the activity showed decrease in the 3 organs. The possible causes of these decreases are discussed.

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Remerciements. Nous remercions MM. les ProfesseursChevallier et Jost de nous avoir permis d'utiliser certains appareils de leur laboratoire.     

Identification of a major cytokinin in coconut milk

A major cytokinin found in coconut milk was isolted by using the tobacco callus growth-promoting assay as a guide during purification. The structure of the factor was determined to be 14-O-{3-O-[-d-galactopyranosyl-(12)--d--galactopyranosyl-(13)--L-arabinofuranosyl]-4-O-(-L-arabinofuranosyl)--d-galactopyranosyl}-trans-zeatin riboside [G₃A₂-ZR] by various NMR techniques, including heteronuclear multiple bond connectivity by 2D multiple quantum NMR (HMBC), as well as mass spectroscopy and sugar analysis. The optimum concentration of G₃A₂-ZR for cytokinin activity in the tobacco callus assay was estimated to be 5×10^–6 M, so that G₃A₂-ZR is one order of magnitude more potent than 1,3-diphenylurea and one order less potent than zeatin riboside. At least 20% of the cytokinin activity of coconut milk could be attributed to G₃A₂-ZR.     

The rate limiting control of enzymes monoamine oxidase and catechol-O-methyl transferase in the foetus and the adult by adreno-cortical hormones

Résumé L'inactivation du cortex surrénal par l'hypophysectomie provoque une augmentation des activités MAO et COMT. L'administration d'ACTH ou d'hydrocortisone réduit l'augmentation des activités enzymatiques chez les foetus décapités sacrifiés à 31 jours. Chez des jeunes rats de 10 jours, surrénalectomisés à la naissance, on constate une augmentation de l'activité MAO dans le cur et l'hypophyse. Chez le rat adulte, l'inhibition de la synthèse des glucocorticoides par la métopirone est également suivie par une augmentation rapide et hautement significative de l'activité de ces deux enzymes dans la plupart des organes.     

Evidence for the extranuclear localization of thymosins in thymus

A new radioimmunoassay has been developed for thymosin ₄ by generating rabbit polyclonal antibodies against the synthetic N-terminal peptide fragment 1–15 coupled to KLH. The synthetic analogue [Tyr¹²]-thymosin ₄ (1–15) was used as tracer. This radioimmunoassay, with a useful range of 10–1000 pmoles, showed cross-reactivity with the second homologous -thymosin of man and rat (thymosin ₁₀) but not of calf (thymosin ₉). This radioimmunoassay, together with an improved radioimmunoassay for the N-terminus of parathymosin , was employed for the measurement of the levels of thymosin ₄ and parathymosin in nuclear and extranuclear extracts of calf thymus. The bulk of these polypeptides was found in the extranuclear material whereas only traces were observed in the nuclear environment, which indicates the extranuclear localisation of - and -thymosins.     

Hypertension expérimentale et protéines sériques

Summary The authors investigated the distribution of serum proteins, especially the ₂ fraction, in rats with artificially induced hypertension (A), in similar rats made normotone by choline-free diet (B), and in a control group (C). A rise in the ₂ fraction of groupA andB was found, without a significant change of the other serum proteins.     

Neurosteroid enhances glutamate release in rat prelimbic cortex via activation of α1-adrenergic and σ1 receptors

The present paper studied the effect and mechanism of neurosteroid pregnenolone sulfate (PREGS) on spontaneous glutamate release using electrophysiological and biochemical methods combined with a pharmacological approach. The results suggested that PREGS had a selective enhancing effect on spontaneous glutamate release in the prelimbic cortex and the hippocampus but not in the striatum. The effect of PREGS in the prelimbic cortex appeared to be via modulation of ₁-adrenergic and ₁ receptors, but in the hippocampus it might be dependent on ₁ receptors only. The activation of ₁-adrenergic receptors synergized ₁ receptor activation in the prelimbic cortex. Intracellular calcium released from the endoplasmic reticulum, protein kinase C, adenylyl cyclase and protein kinase A played a key role in the effect of PREGS. Intracellular calcium, protein kinase C and adenylyl cyclase might be upstream events in the activation of protein kinase A after PREGS.Received 7 January 2005; received after revision 19 February 2005; accepted 22 February 2005 Available online 29 March 2005     

Singlet oxygen reactivity of bilirubin and related tetrapyrroles

Summary The rates of chemical reactivity (k_R) and physical quenching (k_Q) of singlet oxygen by bilirubin IX, mesobilirubin IX, bilirubin IX dimethyl ester, aetiobilirubin IV, biliverdin IX, biliverdin IX dimethyl ester, aetiobiliverdin IV and an oxodipyrromethene have been determined. The k_R and k_Q values approach the diffusion threshold for the bilirubin-like substrates, but k_RQ by about a factor of 10³ for the verdins. A reaction mechanism involving superoxide ion is suggested. Bilirubin appears to quench singlet oxygen by an electron-transfer mechanism.The authors wish to thank the National Science Foundation (CHE 74-20877) and the National Institute of Child Health (HD 09026) for generous support of this work.     

Heavy incorporation of3H-prostaglandin F2α in the neoplastic cells as revealed by autoradiographic studies

Summary A marked uptake (9-fold) of the³H-PGF₂ was found specifically over heterochromatin in the nuclei of neoplastic cells. Lower but significant uptakes of³H-PGF₂ were also found in the nuclei of control epidermal cells, which indicate the presence of nuclear receptors in the epidermal neoplastic cells.     

The chemistry of the polymyxin antibiotics

Zusammenfassung Die Chemie der Polymyxine, einer Klasse von basischen Polypeptid-Antibiotika, begann 1954, als durch Gegenstromverteilung erstmals ein definierter Vertreter, das Polymyxin B₁ in reiner Form isoliert werden konnte (L. C.Craig). Partialhydrolyse mit Mineralsäuren führte zum Schluss, dass es sich um Cyclohepta- oder Cyclooctapeptide mit Seitenketten handelt, die, -Diaminobuttersäure (Dab) enthalten (W.Hausmann).Amidartige Verknüpfung der Seitenkette mit einer Fettsäure [(+)-6-Methyloctansäure (MOA) oder 6-Methylheptansäure (IOA)] (S.Wilkinson) verleiht diesen Antibiotika den Charakter von Invertseifen. Sie sind besonders gegen gramnegative Erreger wirksam. Schwierigkeiten bereiteten die Aufklärung der Verknüpfungsweise der Seitenkette (- oder-) und die Beantwortung der Frage, ob das Molekül nebend-Phenylalanin in der Ringsequenz noch einend-, -Diaminobuttersäurerest in Nachbarschaft zur Fettsäure in der Seitenkette enthält. Synthetische Versuche mitd-, -Diaminobuttersäure an dieser Stelle führten zu hochaktiven Produkten, die aber mit natürlichem Polymyxin B₁ nicht identisch waren. Entscheidende Fortschritte wurden mit dem bakteriellen Enzym Nagarse (T.Suzuki) erzielt, das schrittweise die Seitenkette bis zum Ringpeptid abbaut. Dabei ergab sich, dass den Polymyxinen die allgemeine Struktur eines Cycloheptapeptides mit-verknüpfter Seitenkette zukommt (Figur 4).Die Polymyxine B₁ E₁ (Colistin A) sowie Circulin A unterscheiden sich voneinander nur durch eine Variation in der gleichen Dipeptidsequenz des 7-gliedrigen Ringes. Die im Polymyxin B₁ vorhandene Dipeptidsequenzd-Phe-l-Leu ist in Polymyxin E₁ (Colistin A) durchd-Leu-l-Leu und in Circulin A durchd-Leu-Ll-Ile ersetzt. Im Polymyxin D₁ ist neben dem Ersatz der entsprechenden Sequenz durchl-Leu-l-Thr noch ein, -Diaminobuttersäurerest der Seitenkette durch eind-Serin ausgetauscht. Die entsprechenden Verbindungen mit dem Index 2 unterscheiden sich von denjenigen mit dem Index 1 durch einen Austausch der (+)-6-Methyloctansäure durch 6-Methylheptansäure.Die Struktur von Polymyxin B₁ E₁ und Circulin A konnte durch Totalsynthese gesichert werden (K.Vogler). Weitere Fortschritte in der Erforschung der Natur der noch unbekannten Vertreter sind in Kürze zu erwarten.     

Interaction of vinblastine analogues with tubulin

Summary Studies of the interaction between vinblastine-like alkaloids and their receptor, i.e. tubulin, are reported. They shed some light on the structure-activity relationships in this medicinally important series: the configurations at C₁₄ and C₁₆ as well as the presence of the methoxycarbonyl group on C₁₆ seem to play an essential role in the determination of biological activity.This work was supported by CNRS (A.T.P. No 3232).We thank Dr D. Pantaloni for interesting discussions, Drs N. and Y. Langlois for discussions and for supplying synthetic material, and Eli Lilly Laboratories for gifts of vinblastine, vincristine and leurosidine.     

Isometachromin,a new cytotoxic sesquiterpenoid from a deep water sponge of the family Spongiidae

Isometachromin (1), a new sesquiterpene-quinone that is related structurally to metachromin C (2), and the known compounds ilimaquinone (3) and and 5-epi-ilimaquinone (4), were isolated from a deep water sponge in the family Spongiidae; the structure of isometachromin was elucidated by spectral methods. Isometachromin exhibits in vitro cytotoxicity against the human lung cancer cell line A 549 (IC₅₀=2.6 g/ml), but not against P 388 murine leukemia (IC₅₀10 g/ml) and also exhibits antimicrobial activity.This research is Harbor Branch Oceanographic Institution (HBOI) contribution number 911. We thank Drs S. A. Pomponi and M. Kelly-Borges (HBOI) for sponge taxonomy, and Dr P. McCarthy and T. Peterson (HBOI) for antimicrobial data.     

The discovery of antidepressants: A winding path

Summary Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, reversal of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

Evaluation of monoaminergic receptors in the genetically epilepsy prone rat

Summary The intensity of sound-induced convulsions in the genetically epilepsy-prone rat (GEPR) was reduced in a dose related fashion by intracerebroventricular administration of dobutamine, (₁ agonist), terbutaline (₂ agonist) or phenylephrine (₁ agonist). BHT-920 (₂ agonist) did not cause a dose-related decrease in sound-induced convulsion intensity. Binding studies showed that whole brain and receptor densities (B_max) were normal while the K_d was increased for the ligand in GEPR brain.Acknowledgment. We are most grateful to Boehringer Ingelheim for generously supplying BHT 920. We are also indebted to Ciba-Geigy Corporation for the gift of terbutaline hydrochloride and phentolamine hydrochloride. The work was supported in part by NIH grant NS 16829.     

Studies on the reconstitution ofP. clarkii blue carotenoprotein from its isolated subunits

Summary A blue carotenoid-protein complex (_max 635 nm) was extracted and purified from the carapace of the crayfishProcambarus clarkii. The complex was further liberated from astaxanthin, its prostetic group, causing dissociation into apoprotein subunits. Reconstitution of the complex from the various sub-units (isolated by chromatofocusing) plus astaxanthin was attempted. Apoprotein-size pigments of rose-purple color (_max 545 nm) were obtained. It was found that both monomers are required in order to a blue complex fairly similar in structure ot the native one. However, the native conformation was not completely recovered, as indicated by some differences in the UV spectrum.     

Renal effects of the inhibitor of thromboxane A2-synthetase OKY-046

Summary Acute renal failure (ARF) was associated with increased urinary thromboxane (TXA₂) excretion and lessened excretion of sodium (U_NaV) and fractional excretion of sodium (FE_Na%). The inhibitor of thromboxane A₂-synthetase OKY-046 enhanced sodium excretion and fractional excretion of sodium in normal and saline loaded animals whereas it partially prevented the reduction in sodium excretion and creatinine clearance and significantly increased fractional excretion of sodium in glycerol treated rats suggesting a partial protection against the development of acute renal failure.Acknowledgment. This work was supported by the Public Benefit Foundation Alexander S. Onassis (G-73). We thank ONO Pharmaceutical Co. Ltd, Kissei Pharmaceutical Co. Ltd, Osaka, Japan, and Dr A Hornych for their generous donations of OKY-046 and anti6keto-PGF_1a antibodies respectively.     

A postsynaptic α, 2-receptor: The alpha-adrenergic receptor of hamster white fat cells

Summary The effects of selected -agonists and -antagonists on theophylline-induced lipolysis were investigate in isolated hamster white fat cells ₂-Agonists (tramazoline, clonidine) inhibited theophylline-induced lipolysis while an ₂-agonist (methoxamine) was without any effect. The inhibitory effect of ₂-agonists was suppressed by yohimbine (₂-antagonist), whereas ₂-antagonists were inefficient. This result implies that the -adrenergic receptor of hamster fat cells is of the ₂-type, although located postsynaptically.Acknowledgments. This work was supported by grants from CNRS (ERA 412) and DGRST (grant No. 787 1078). We thank M. Dauzats for excellent technical assistance. We thank Prof. H. Schmitt for tramazoline and AR-C 239 and for helpful discussion.