Effects of (8β)-8-[(Methylthio)methyl]-6-propylergoline on dopaminergic function and brain dopamine turnover in rats

Fuller, Ray W.; Clemens, James A.; Kornfeld, Edmund C.; Snoddy, Harold D.; Smalstig, E. Barry; Bach, Nicholas J.

doi:10.1016/0024-3205(79)90334-5

Cited by 108 publications

(27 citation statements)

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“…Serum corticosterone elevation by pergolide in rats: prevention of tolerance development by spiperone pergolide mesylate, a dopamine agonist (Fuller et al 1979), causes an acute elevation of serum corticosterone Concentration in rats (Fuller & Snoddy 1981a). After repeated administration of pergolide, the acute elevation of serum corticosterone is absent or greatly attenuated (Fuller & Snoddy 1981b).…”

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confidence: 99%

Serum corticosterone elevation by pergolide in rats: prevention of tolerance development by spiperone

Fuller

Snoddy

1982

Journal of Pharmacy and Pharmacology

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confidence: 99%

Serum corticosterone elevation by pergolide in rats: prevention of tolerance development by spiperone

Fuller

Snoddy

1982

Journal of Pharmacy and Pharmacology

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Section: Introductionmentioning

confidence: 99%

“…The long duration of action of pergolide as an agonist (9, 10) prompted us to investigate its therapeutic effectiveness in parkinsonism patients. Preliminary reports on this study have been presented (9,11,12 Values for the mean inhibitory concentration, ICso, were derived by log probit analysis. Values for the dissociation constant, Kd, for each radioactive ligand were determined from the corresponding Scatchard plots, and values for the inhibitor constant, Ki, were determined according to the equation Ki = IC50/(I + C/Kd), in which C represents the concentration of the radioactive ligand.…”

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Interaction of pergolide with central dopaminergic receptors.

Goldstein¹,

Lieberman²,

Lew³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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The activity of pergolide, an N-propylergoline derivative, has been tested for stimulation of central dopaminergic receptors. Binding to dopamine receptors shows that pergolide acts as an agonist with respect to these receptors. GTP decreases the potencies of dopamine agonists and of pergolide, It is now established that the major abnormality in parkinsonism is the degeneration of the nigrostriatal 3,4-dihydroxyphenylethylamine (dopamine) neurons. The effectiveness of 3,4-dihydroxyphenylalanine (L-dopa) in parklnsonism is dependent on the capacity of the remaining nigrostriatal dopamine neurons to synthesize dopamine from administered L-dopa. It has become apparent that therapeutic response diminishes after prolonged treatment with L-dopa (1, 2). This decrease might be due to progressive degeneration of the nigrostriatal dopamine neurons or to a decreased sensitivity of dopamine receptors in the striatum. It was therefore of interest to investigate the effectiveness of drugs that directly stimulate dopamine receptors in the brain. Among various dopamine agonists tested, certain ergot alkaloids were found to stimulate dopamine receptors (3, 4), and their therapeutic effectiveness in parkinsonism was investigated (5, 6).We now describe dopamine agonist properties of a semisynthetic ergoline derivative, pergolide (8fl-[8-(methylthio)-methyl]-6-propylergoline), tested both in vitro and in two animal models that simulate certain features of parkinsonism. The potency of pergolide was compared with that of bromocriptine (2-bromo-a-ergocriptine), another ergot derivative currently used in the treatment of parkinsonism (7,8). The long duration of action of pergolide as an agonist (9, 10) prompted us to investigate its therapeutic effectiveness in parkinsonism patients. Preliminary reports on this study have been presented (9,11,12). MATERIALS AND METHODSNPA) (75 Ci/nmol) were purchased from New England Nuclear (1 Ci = 3.7 X 1010 becquerels). Pergolide was a gift from Eli Lilly, and bromocriptine from Sandoz Pharmaceutical.Binding Assay. Preparation of bovine or rat membranes and the ensuing binding assay were carried out as described (13). For routine assay each tube contained 1.8 ml. of membrane suspension (5 mg of wet tissue), 0. Values for the mean inhibitory concentration, ICso, were derived by log probit analysis. Values for the dissociation constant, Kd, for each radioactive ligand were determined from the corresponding Scatchard plots, and values for the inhibitor constant, Ki, were determined according to the equation Ki =

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“…The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating cross-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.Pergolide mesylate, a dopamine agonist shown to pro duce various dopaminergic effects in animals [4,5,12] and to be effective in treating hyperprolactinemia and Parkin son's disease in humans (3, 11, 13] has been reported to cause an acute elevation of serum corticosterone concentra tion in rats [7], This elevation disappears or is severely atten uated after repeated daily administration of pergolide [8].Evidence that the elevation of serum corticosterone resulted from activation of central dopaminergic receptors included the findings that other dopamine agonists mimicked the ef fect and that centrally acting (haloperidol, spiperone) but not peripherally acting (domperidone) dopamine antago nists blocked the effect [7], A close structural analog of per golide, containing an N-methyl substituent in place of the N-n-propyl substituent that is in pergolide ( fig. 1), did not elevate serum corticosterone at a dose (1 mg/kg, i.p.)…”

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Elevation of Serum Corticosterone in Rats by Dopamine Agonists Related in Structure to Pergolide

et al. 1983

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Two chemical analogs of pergolide were examined to test further the idea that pergolide elevates serum corticosterone concentration in rats by activation of brain dopaminergic receptors. LY116467, which contains an N-methyl substituent in place of the N-n-propyl substituent in pergolide, was less potent than pergolide in lowering brain levels of 3,4-dihydroxyphenylacetic acid (Dopac), the metabolite of dopamine. LY 116467 increased serum corticosterone concentration in rats at a dose of 3 mg/kg (a higher dose than is required for pergolide), and the effect was prevented by spiperone pretreatment. LY141865, which has been reported to differ from pergolide in not activating dopamine-sensitive adenylate cyclase and which was found in this study to have much less affinity for serotonin receptors than does pergolide, increased serum corticosterone in much the same manner as pergolide, only slightly higher doses being required. The effect of LY141865 was prevented by pretreatment with haloperidol but not domperidone. Both haloperidol and domperidone increased serum prolactin concentration when given alone or in combination with LY141865, indicating they were both capable of blocking peripheral (pituitary) dopamine receptors. In contrast, haloperidol but not domperidone caused a marked elevation in brain levels of Dopac and of homovanillic acid and prevented the lowering of these brain dopamine metabolites by LY141865. The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating cross-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.

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Effects of (8β)-8-[(Methylthio)methyl]-6-propylergoline on dopaminergic function and brain dopamine turnover in rats

Cited by 108 publications

References 11 publications

Serum corticosterone elevation by pergolide in rats: prevention of tolerance development by spiperone

Serum corticosterone elevation by pergolide in rats: prevention of tolerance development by spiperone

Interaction of pergolide with central dopaminergic receptors.

Elevation of Serum Corticosterone in Rats by Dopamine Agonists Related in Structure to Pergolide

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