title: Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors.
abstract: Cardiac-valve regurgitation observed in Parkinson patients treated with the ergoline dopamine receptor agonist 8beta-methylthiomethyl-6-propylergoline (pergolide) has been associated with the agonist efficacy of the drug at 5-hydroxytryptamine(2B) (5-HT(2B)) receptors. 5-HT(2A) receptors may also play a role in pergolide-induced cardiac-valve regurgitation. We studied the pharmacological profile of pergolide and eight derivatives in porcine vascular rings endowed with 5-HT(2B) and 5-HT(2A) receptors to detect the molecular fragment of the pergolide molecule that may be responsible for agonism at these receptors. Pergolide derivatives showed a different substitution pattern at N(6), and the side chain at C(8) was modified by replacement of the sulfur against an oxygen atom. We demonstrate that the potent agonism of pergolide both at 5-HT(2B) and 5-HT(2A) receptors is retained when the N(6) propyl substituent is replaced by ethyl. However, agonism can be converted into antagonism if N(6) propyl is replaced by methyl. The N(6)-unsubstituted derivative was a low efficacy 5-HT(2B) receptor partial agonist and a 5-HT(2A) receptor antagonist. This pharmacological pattern was also applicable for pergolide congeners with an oxygen in the side chain at C(8). 6-Methylpergolide retained agonist efficacy and potency compared with pergolide at human (h) D(2LONG(L)) and hD(2SHORT(S)) receptors as determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Based on the ability of pergolide to produce potent agonism at 5-HT(2B) receptors and the failure of 6-methylpergolide to act as an agonist but as a potent antagonist, we conclude that the N(6) propyl substituent of pergolide is crucial for 5-HT(2B) receptor agonism and thus a determinant of valvular regurgitation.
authors: Institute of Pharmacy, Free University of Berlin, Königin-Luise-Str. 2 + 4, 14195 Berlin, Germany.
authors: Tilo
authors: T
authors: Görnemann
authors: Harald
authors: H
authors: Hübner
authors: Peter
authors: P
authors: Gmeiner
authors: Reinhard
authors: R
authors: Horowski
authors: Klaus Peter
authors: KP
authors: Latté
authors: Miroslav
authors: M
authors: Flieger
authors: Heinz H
authors: HH
authors: Pertz
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015394:Molecular Structure; D010479:Pergolide / Q000737:chemistry* / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D010479:Pergolide