title: Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human alpha(2)-adrenoceptors: cellular and functional characterization.
abstract: Compared with cloned, human (h)D(2) receptors (pK(i) = 6.9), the antiparkinsonian agent piribedil showed comparable affinity for halpha(2A)- (7.1) and halpha(2C)- (7.2) adrenoceptors (ARs), whereas its affinity for halpha(2B)-ARs was less marked (6.5). At halpha(2A)- and halpha(2C)-ARs, piribedil antagonized induction of [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) binding by norepinephrine (NE) with pK(b) values of 6.5 and 6.9, respectively. Furthermore, Schild analysis of the actions of piribedil at halpha(2A)-ARs indicated competitive antagonism, yielding a pA(2) of 6.5. At a porcine alpha(2A)-AR-Gi1alpha-Cys351C (wild-type) fusion protein, piribedil competitively abolished (pA(2) = 6.5) GTPase activity induced by epinephrine. However, at a alpha(2A)-AR-Gi1alpha-Cys351I (mutant) fusion protein of amplified sensitivity, although still acting as a competitive antagonist (pA(2) = 6.2) of epinephrine, piribedil itself manifested weak partial agonist properties. Similarly, piribedil weakly induced mitogen-activated protein kinase phosphorylation via wild-type halpha(2A)-ARs, although attenuating its phosphorylation by NE. As demonstrated by functional [(35)S]GTPgammaS autoradiography in rats, piribedil antagonized activation by NE of alpha(2)-ARs in cortex, amygdala, and septum. Antagonist properties were also expressed in a dose-dependent enhancement of the firing rate of adrenergic neurons in locus ceruleus (0.125-4.0 mg/kg i.v.). Furthermore, piribedil (2.5-4.0 mg/kg s.c.) accelerated hippocampal NE synthesis, elevated dialysis levels of NE in hippocampus and frontal cortex, and blocked hypnotic-sedative properties of the alpha(2)-AR agonist xylazine. Finally, piribedil showed only modest affinity for rat alpha(1)-ARs (5.9) and weakly antagonized NE-induced activation of phospholipase C via halpha(1A)-ARs (pK(b) = 5.6). In conclusion, piribedil displays essentially antagonist properties at cloned, human and cerebral, rat alpha(2)-ARs. Blockade of alpha(2)-ARs may, thus, contribute to its clinical antiparkinsonian profile.
authors.affiliation: Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France. mark.millan@fr.netgrs.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: D
authors.initials: D
authors.lastname: Cussac
authors.forename: G
authors.initials: G
authors.lastname: Milligan
authors.forename: C
authors.initials: C
authors.lastname: Carr
authors.forename: V
authors.initials: V
authors.lastname: Audinot
authors.forename: A
authors.initials: A
authors.lastname: Gobert
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: J M
authors.initials: JM
authors.lastname: Rivet
authors.forename: M
authors.initials: M
authors.lastname: Brocco
authors.forename: D
authors.initials: D
authors.lastname: Duqueyroix
authors.forename: J P
authors.initials: JP
authors.lastname: Nicolas
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010891:Piribedil / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000978:Antiparkinson Agents; D010716:Phosphatidylinositols; D018341:Receptors, Adrenergic, alpha-2; D011993:Recombinant Fusion Proteins; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010891:Piribedil; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D009638:Norepinephrine