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Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human alpha2-adrenoceptors: cellular and functional characterization. PDF

Millan MJ, Cussac D, Milligan G, Carr C, Audinot V, Gobert A, Lejeune F, Rivet JM, Brocco M, Duqueyroix D, Nicolas JP, Boutin JA, Newman-Tancredi A.
J Pharmacol Exp Ther. 2001 Jun;297(3):876-87.

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Compared with cloned, human (h)D2 receptors (pKi = 6.9), the antiparkinsonian agent piribedil showed comparable affinity for halpha2A- (7.1) and halpha2C- (7.2) adrenoceptors (ARs), whereas its affinity for halpha2B-ARs was less marked (6.5). At halpha2A- and halpha2C-ARs, piribedil antagonized induction of [35S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) binding by norepinephrine (NE) with pKb values of 6.5 and 6.9, respectively. Furthermore, Schild analysis of the actions of piribedil at halpha2A-ARs indicated competitive antagonism, yielding a pA2 of 6.5. At a porcine alpha2A-AR-Gi1alpha-Cys351C (wild-type) fusion protein, piribedil competitively abolished (pA2 = 6.5) GTPase activity induced by epinephrine. However, at alpha2A-AR-Gi1alpha-Cys351I (mutant) fusion protein of amplified sensitivity, although still acting as a competitive antagonist (pA2 = 6.2) of epinephrine, piribedil itself manifested weak partial agonist properties. Similarly, piribedil weakly induced mitogen-activated protein kinase phosphorylation via wild-type halpha2A-ARs, although attenuating its phosphorylation by NE. As demonstrated by functional [35S]GTPgammaS autoradiography in rats, piribedil antagonized activation by NE of alpha2-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 alpha2-AR agonist xylazine. Finally, piribedil showed only modest affinity for rat alpha1-ARs (5.9) and weakly antagonized NE-induced activation of phospholipase C via halpha1A-ARs (pKb = 5.6). In conclusion, piribedil displays essentially antagonist properties at cloned, human and cerebral, rat alpha2-ARs. Blockade of alpha2-ARs may, thus, contribute to its clinical antiparkinsonian profile.