Ergot alkaloids. Ergolines and related compounds as inhibitors of prolactin release

Cassady, John M.; Li, George S.; Spitzner, Ernest B.; Floss, Heinz G.; Clemens, James A.

doi:10.1021/jm00249a009

Cited by 45 publications

(15 citation statements)

References 19 publications

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“…The exact reason for the fact that edematization was only observed in the Copenhagen strain is obscure. However, this strain of rats has been found to be unique in other respects as well, eg, the spontaneous appearance of prostatic adenocarcinoma [27] and a control prolactin blood concentration in the Copenhagen castrated rat ten times higher (Table 11) than that normally found in other strains [7]. Furthermore, we have observed a clearly higher prolactin blood concentration in the Copenhagen rats than in the estrogen-insensitive Wistar-Furth strain, which had normal values.…”

Section: Discussionsupporting

confidence: 50%

Fluid imbibition as a factor in estrogen‐induced increase of prostatic weight in castrated rats

et al. 1981

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The mechanism by which estrogens inhibit castration atrophy has been investigated morphologically and biochemically utilizing ventral prostate from Copenhagen rats. The suppression of weight loss and gross edematous appearance of the prostate associated with the in vivo effect of 17 beta-estradiol (E2) could not be accounted for by DNA and protein synthesis. Increase in the fluid content in the tissues was confirmed by demonstration of significant increase in the ratio of wet/dry tissue weights. Light microscopy demonstrated that the main effects were on the stroma, characterized by large interglandular areas almost totally devoid of collagen resulting in an edematous appearance. Electron microscope studies showed an abundance of fluid localized adjacent to the capillary endothelium and some red blood cells indicating disturbances in capillary permeability. The combination of a prolactin secretion inhibiting agent with E2 alone, indicating an involvement of prolactin the estrogen effect. Differences in blood prolactin concentration between the strains of rats may influence the sensitivity of the prostate to estrogens.

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Section: Discussionsupporting

confidence: 50%

Fluid imbibition as a factor in estrogen‐induced increase of prostatic weight in castrated rats

et al. 1981

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“…We note that the alkaloid profiles of plants with the knockoff strains are similar to those of some naturally occurring grass- Epichloë species symbiota that accumulate chanoclavine as an end product ( Schardl et al 2013c ). In rats, chanoclavine I exhibits no appreciable effect on dopamine receptors ( Watanabe et al 1987 ) and prolactin levels ( Cassady et al 1974 ). Ergotryptamine is a newly identified ergot alkaloid ( Ryan et al 2015 ) for which the biological activities are yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Chromosome-End Knockoff Strategy to Reshape Alkaloid Profiles of a Fungal Endophyte

Florea

Phillips

Panaccione

et al. 2016

G3 Genes|Genomes|Genetics

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Molecular genetic techniques to precisely eliminate genes in asexual filamentous fungi require the introduction of a marker gene into the target genome. We developed a novel strategy to eliminate genes or gene clusters located in subterminal regions of chromosomes, and then eliminate the marker gene and vector backbone used in the transformation procedure. Because many toxin gene clusters are subterminal, this method is particularly suited to generating nontoxic fungal strains. We tested this technique on Epichloë coenophiala, a seed-transmissible symbiotic fungus (endophyte) of the important forage grass, tall fescue (Lolium arundinaceum). The endophyte is necessary for maximal productivity and sustainability of this grass but can produce ergot alkaloids such as ergovaline, which are toxic to livestock. The genome sequence of E. coenophiala strain e19 revealed two paralogous ergot alkaloid biosynthesis gene clusters, designated EAS1 and EAS2. EAS1 was apparently subterminal, and the lpsB copy in EAS2 had a frame-shift mutation. We designed a vector with a fungal-active hygromycin phosphotransferase gene (hph), an lpsA1 gene fragment for homologous recombination at the telomere-distal end of EAS1, and a telomere repeat array positioned to drive spontaneous loss of hph and other vector sequences, and to stabilize the new chromosome end. We transformed E. coenophiala with this vector, then selected “knockoff” endophyte strains, confirmed by genome sequencing to lack 162 kb of a chromosome end including most of EAS1, and also to lack vector sequences. These ∆EAS1 knockoff strains produced no detectable ergovaline, whereas complementation with functional lpsB restored ergovaline production.

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“…in toluene added and the resultant mixture heated at reflux for 18 h. Work‐up and purification by flash chromatography gave octahydroquinoline 14a in 60 % yield (Scheme ). Pleasingly, the literature yields for construction of related octahydroquinolines were similar 28,31…”

Section: Resultsmentioning

confidence: 90%

“…The synthetic strategy hinges on a successful one‐pot cyclisation to set up an octahydroquinoline core using ethyl α‐(bromomethyl)acrylate ( 12 ), cyclohexanone and various primary amines 13 to vary the substitution on the alkaloid nitrogen. The strategy is based on a method used by both Horii et al27 and Cassady et al28 who constructed a tetracyclic ergot alkaloid core by reaction of a highly substituted cyclohexanone with ethyl α‐(bromomethyl)acrylate ( 12 ) and methylamine. The present work tests the generality of this one‐pot cyclisation as a method to afford an octahydroquinoline core by reaction of simple cyclohexanone with a range of primary amines (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

et al. 2009

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The synthesis of AE and BE analogues of the alkaloid methyllycaconitine is reported. The analogues contain two key pharmacophores: a 2‐(2‐methylmaleimido)benzoate ester and a homocholine motif formed from a tertiary N‐(3‐phenylpropyl)amine incorporated into either a 3‐azabicyclo[3.3.1]nonane (AE) or octahydroquinoline (BE) ring system. An additional aromatic group is introduced into the AE bicyclic system using a Horner–Wadsworth–Emmons reaction. The BE analogues are synthesised by a one‐pot cyclisation using ethyl α‐(bromomethyl)acrylate, a primary amine and cyclohexanone leading to an efficient assembly of an octahydroquinoline ring system that mimics the BE‐rings of methyllycaconitine. In both the AE and BE analogues, the key 2‐(2‐methylsuccinimido)benzoate ester pharmacophore is introduced by esterification of the alcohol precursors with 2‐(2‐methylmaleimido)benzoic acid (10) under Steglich conditions followed by hydrogenation over palladium on charcoal.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Ergot alkaloids. Ergolines and related compounds as inhibitors of prolactin release

Cited by 45 publications

References 19 publications

Fluid imbibition as a factor in estrogen‐induced increase of prostatic weight in castrated rats

Fluid imbibition as a factor in estrogen‐induced increase of prostatic weight in castrated rats

Chromosome-End Knockoff Strategy to Reshape Alkaloid Profiles of a Fungal Endophyte

Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

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