Lisurid

Structural formula
General
Non-proprietary name	Lisurid
other names	1,1-Diethyl-3- (9,10-didehydro-6-methyl-8 α -ergolinyl) urea
Molecular formula	C 20 H 26 N 4 O; C 20 H 26 N 4 O · C 4 H 8 O 4 ( maleate );
External identifiers / databases
ECHA InfoCard	100,038,099
PubChem	28864
DrugBank	DB00589
Wikidata	Q424446
Drug information
ATC code	N02 CA07 G02 CB02
Drug class	Dopamine agonist , serotonin agonist , 5-HT2B - antagonist
properties
Molar mass	338.45 g · mol -1 ; 454.52 g · mol -1 ( maleate );
Melting point	186 ° C ; 200 ° C (decomposition) ( maleate );
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances danger
H and P phrases	H: 300-310-330
	P: ?
Toxicological data	12.5 mg kg −1 ( LD 50 , rat , oral , maleate) ; 1.5 mg kg −1 ( LD 50 , rat , iv , maleate) ; 90 mg kg −1 ( LD 50 , mouse , oral , maleate) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Lisuride is a drug that is used in the therapy of Parkinson's disease , in the prophylaxis of migraines and as a prolactin inhibitor for weaning . Lisurid is sold in Germany under the brand name Dopergin ^® and is subject to medical prescription .

chemistry

Lisuride is a drug derived from ergot alkaloids with an ergoline skeleton . However, it differs from naturally occurring ergolines, such as. B. Ergotamine , through an (8 S ) configuration in the ergoline framework.

With terguride and mesulergine , two structurally related compounds of lisuride are known that have been clinically tested.

Lisuride is prepared by Hofmann , Curtius or Lossen degradation of lysergic acid , subsequent racemate separation and acylation of the (8 S ) -amino group with diethylcarbamoyl chloride.

pharmacology

application areas

Lisuride was developed as a migraine prophylactic. There is no longer any approval for this indication in Germany. Lisuride is now used primarily in combination with levodopa in patients with Parkinson's disease . Further areas of application are restless legs syndrome , neuroleptic malignant syndrome , primary and secondary weaning , galactorrhea , prolactin-related amenorrhea and acromegaly .

Mechanism of action

Lisuride, like many ergolines, is considered a "dirty drug" because it interacts with many receptors , including dopamine receptors , serotonin receptors and adrenoceptors . In contrast to all other therapeutically used ergot alkaloid derivatives, lisuride also shows a high affinity for histamine receptors and beta-adrenoceptors .

An interaction with dopamine receptors is held responsible for its clinical effectiveness in the treatment of Parkinson's disease. Lisuride acts as a partial agonist ( dopamine agonist ) on the dopamine receptors of subtypes D _2/3/4 and also subtypes D _1/5 and can thus eliminate the dopamine deficiency symptoms of Parkinson's disease. In addition, lisuride-induced stimulation of dopamine receptors in the pituitary gland inhibits the release of the hormone prolactin and thus inhibits milk production.

Lisuride acts as an antagonist at serotonin receptors of the subtype 5-HT _2B . Its effectiveness in migraine prophylaxis is linked to an inhibition of these receptors. To the serotonin receptors subtype 5-HT _1A and 5-HT _{2A / C} it acts as a partial agonist . Lisuride has an affinity for the serotonin receptors of the subtype 5-HT _{1B / D} , but whether it acts as an agonist or an antagonist is not clear.

Side effects

Nausea, tiredness, drowsiness, dizziness, headache, sweating, dry mouth and a sudden drop in blood pressure as well as, in rare cases, vomiting and retroperitoneal fibrosis may occur, particularly at the beginning of therapy, when the dose is too high or when the dose is increased, or when taken without a meal at the same time .

In animal experiments lisuride dissolves in male rats a premature ejaculation from. In female and early castrated male rats, administration of lisuride leads to the development of male behavior patterns shortly after birth or during puberty .

Interactions

The sedative effect of the preparation can be increased by other drugs that have a depressant effect on the central nervous system. With simultaneous use with neuroleptics and other dopamine antagonists, a mutual weakening of the effect is to be expected.

Trade names

Lisuride is commercially available in Germany and Austria under the name Dopergin.

Individual evidence

^ ^A ^b The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 956-957, ISBN 978-0-911910-00-1 .
↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of Lisuride in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was accessed on June 10, 2020, is reproduced from a self-classification by the distributor .
↑ ^a ^b ^c Entry on Lisuride maleate in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on June 10, 2020.
↑ Hans-Jörg Assion: Neuroleptic Malignant Syndrome. Georg Thieme Verlag, 2004, ISBN 978-3-131-33171-7 , p. 33 ( limited preview in the Google book search).
↑ ^a ^b Millan, MJ et al. (2002): Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . In: J Pharmacol Exp Ther . , 303 (2), 791-804; PMID 12388666 ; PDF (free full text access).
↑ Jähnichen S, Horowski R, Pertz HH: Agonism at 5-HT2B receptors is not a class effect of the ergolines . In: Eur. J. Pharmacol. . 513, No. 3, April 2005, pp. 225-8. doi : 10.1016 / j.ejphar.2005.03.010 . PMID 15862804 .
↑ Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H: Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? . In: The European Journal of Neuroscience . 8, No. 5, May 1996, pp. 959-67. doi : 10.1111 / j.1460-9568.1996.tb01583.x . PMID 8743744 .
↑ Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE: Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats . In: Psychopharmacology (Berl.) . 164, No. 1, October 2002, pp. 93-107. doi : 10.1007 / s00213-002-1141-z . PMID 12373423 .
↑ Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M: Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors . In: Psychopharmacology (Berl.) . 136, No. 4, April 1998, pp. 409-14. doi : 10.1007 / s002130050585 . PMID 9600588 .
↑ Mark J. Millan, Lisa Maiofiss, Didier Cussac, Valerie Audinot, Jean-A. Boutin, Adrian Newman-Tancredi: Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . In: The Journal of pharmacology and experimental therapeutics . 303, No. 2, November 2002, pp. 791-804. doi : 10.1124 / jpet.102.039867 . PMID 12388666 .
^ L. Napoli-Farris, W. Fratta, GL Gessa: Stimulation of dopamine autoreceptors elicits "premature ejaculation" in rats. In: Pharmacology, Biochemistry and Behavior . Volume 20, Number 1, January 1984, pp. 69-72, PMID 6695002 .
↑ Z. Hlinák, J. Madlafousek, I. Krejcí: Effects of lisuride on precopulatory and copulatory behavior of adult male rats. In: Psychopharmacology. Volume 79, Numbers 2-3, 1983, pp. 231-235, PMID 6405433 .
↑ F. Götz, R. Tönjes, J. Maywald, G. Dörner: Short- and long-term effects of a dopamine agonist (lisuride) on sex-specific behavioral patterns in rats. In: Experimental and clinical endocrinology. Volume 98, Number 2, 1991, pp. 111-121, doi : 10.1055 / s-0029-1211107 . PMID 1778225 .

[MERCK_Index-1] A ^b The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 956-957, ISBN 978-0-911910-00-1 .

[2] Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of Lisuride in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was accessed on June 10, 2020, is reproduced from a self-classification by the distributor .

[chemid-3] Entry on Lisuride maleate in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on June 10, 2020.

[4] Hans-Jörg Assion: Neuroleptic Malignant Syndrome. Georg Thieme Verlag, 2004, ISBN 978-3-131-33171-7 , p. 33 ( limited preview in the Google book search).

[Millan-5] Millan, MJ et al. (2002): Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . In: J Pharmacol Exp Ther . , 303 (2), 791-804; PMID 12388666 ; PDF (free full text access).

[Jähnichen_et_al._(2005)-6] Jähnichen S, Horowski R, Pertz HH: Agonism at 5-HT2B receptors is not a class effect of the ergolines . In: Eur. J. Pharmacol. . 513, No. 3, April 2005, pp. 225-8. doi : 10.1016 / j.ejphar.2005.03.010 . PMID 15862804 .

[pmid8743744-7] Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H: Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? . In: The European Journal of Neuroscience . 8, No. 5, May 1996, pp. 959-67. doi : 10.1111 / j.1460-9568.1996.tb01583.x . PMID 8743744 .

[8] Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE: Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats . In: Psychopharmacology (Berl.) . 164, No. 1, October 2002, pp. 93-107. doi : 10.1007 / s00213-002-1141-z . PMID 12373423 .

[9] Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M: Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors . In: Psychopharmacology (Berl.) . 136, No. 4, April 1998, pp. 409-14. doi : 10.1007 / s002130050585 . PMID 9600588 .

[10] Mark J. Millan, Lisa Maiofiss, Didier Cussac, Valerie Audinot, Jean-A. Boutin, Adrian Newman-Tancredi: Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . In: The Journal of pharmacology and experimental therapeutics . 303, No. 2, November 2002, pp. 791-804. doi : 10.1124 / jpet.102.039867 . PMID 12388666 .

[11] L. Napoli-Farris, W. Fratta, GL Gessa: Stimulation of dopamine autoreceptors elicits "premature ejaculation" in rats. In: Pharmacology, Biochemistry and Behavior . Volume 20, Number 1, January 1984, pp. 69-72, PMID 6695002 .

[12] Z. Hlinák, J. Madlafousek, I. Krejcí: Effects of lisuride on precopulatory and copulatory behavior of adult male rats. In: Psychopharmacology. Volume 79, Numbers 2-3, 1983, pp. 231-235, PMID 6405433 .

[13] F. Götz, R. Tönjes, J. Maywald, G. Dörner: Short- and long-term effects of a dopamine agonist (lisuride) on sex-specific behavioral patterns in rats. In: Experimental and clinical endocrinology. Volume 98, Number 2, 1991, pp. 111-121, doi : 10.1055 / s-0029-1211107 . PMID 1778225 .