Interaction of pergolide with central dopaminergic receptors.

Abstract

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 =

Pergolide-Induced Dyspnea, Bilateral Pleural Effusion and Peripheral Edema

“…Pergolide is a short-acting ergot derivative used in the treatment of Parkinson’s disease which acts as a dopamine receptor agonist for D 1 and D 2 receptors [1]. Pleuropulmonary changes due to another dopamine agonist, bromocriptine, were first described in 1981 by Rinne [2]and confirmed later by others [3, 4].…”

Fescue toxicosis and its influence on the rumen microbiome: mitigation of production losses through clover isoflavones

“…The endophyte has been shown to reduce serum prolactin concentrations across species, in cattle (Hemken et al 1979), sheep (Bond et al 1981), and horses (McCann et al 1992). Dopamine is the major prolactininhibiting neurotransmitter and the ability of the endophyte to reduce serum prolactin levels is due in part to the actions of ergot alkaloids on pituitary dopamine receptors (Goldstein et al 1980;Civelli et al 1993;Campbell et al 2014). Administration of a dopamine antagonist to animals affected by fescue consumption increases the circulating levels of prolactin and demonstrates the dopaminergic effect of the alkaloids produced by the endophyte (Lipham et al 1989).…”

Stereochemistry of dopaminergic ergoline derivatives: structures of pergolide and pergolide mesylate

“…Its antiparkinson efficacy, like that of the other ergolines, can be attributed to the postsynaptic stimulation of central dopaminergic receptors (8,9).…”