title: Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: interactions with alpha(1)-, 5-HT(2)- and H(1)-receptors.
abstract: Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, alpha(1A/1B/1D), 5-HT(2A/2B)- and histamine H(1), was investigated using different functional in vitro assays. The drug behaved as an antagonist at alpha(1)-adrenoceptors without the ability to discriminate between the subtypes (pA(2) values: alpha(1A) 7.31; alpha(1B) 7.37; alpha(1D) 7.35) and showed antagonistic properties at the histamine H(1) receptor. In contrast, at serotonergic receptors (5-HT(2A), 5-HT(2B)) proterguride acted as a partial agonist. The drug stimulated 5-HT(2A) receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC(50) 8.34, E(max) 53% related to the maximum response to 5-HT; 5-HT: pEC(50) 7.03). Agonism at 5-HT(2B) receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT(2B) receptors in porcine pulmonary arteries by proterguride (pEC(50) 7.13, E(max) 49%; E(max) (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT(2B) receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.
authors.affiliation: NeuroBiotec GmbH, Tegeler Str. 6, 13353 Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schurad
authors.forename: R
authors.initials: R
authors.lastname: Horowski
authors.forename: S
authors.initials: S
authors.lastname: Jähnichen
authors.forename: T
authors.initials: T
authors.lastname: Görnemann
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.forename: H H
authors.initials: HH
authors.lastname: Pertz
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001158:Arteries / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004873:Ergolines / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D013552:Swine; D013623:Tail / Q000098:blood supply; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D004873:Ergolines; D044403:Receptor, Serotonin, 5-HT2B; D018340:Receptors, Adrenergic, alpha-1; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; C055236:proterguride; D014508:Urea