Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human alpha(2)-adrenoceptors: cellular and functional characterization

• Published in: The Journal of pharmacology and experimental therapeutics 2001-06, Vol.297 (3), p.876-887
• Main Authors: Millan, M J, Cussac, D, Milligan, G, Carr, C, Audinot, V, Gobert, A, Lejeune, F, Rivet, J M, Brocco, M, Duqueyroix, D, Nicolas, J P, Boutin, J A, Newman-Tancredi, A
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists - pharmacology; Animals; Antiparkinson Agents - pharmacology; Binding, Competitive - drug effects; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Frontal Lobe - drug effects; Frontal Lobe - metabolism; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Locus Coeruleus - cytology; Locus Coeruleus - drug effects; Locus Coeruleus - metabolism; Male; Mitogen-Activated Protein Kinases - metabolism; Neurons - drug effects; Neurons - metabolism; Norepinephrine - metabolism; Norepinephrine - pharmacology; Phosphatidylinositols - metabolism; Phosphorylation - drug effects; Piribedil - pharmacology; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2 - genetics; Receptors, Adrenergic, alpha-2 - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Serotonin - metabolism
• ISSN: 0022-3565

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.