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

Compared with cloned. human (h)D-2 receptors (pK(1) = 6.9), the antiparkins onian agent piribedil showed comparable affinity for h(alpha 2A)- (7.1) and h(alpha 2C)- (7.2) adrenoceptors (ARs), whereas its affinity for h(alpha 2 B)-ARs was less marked (6.5). At h(alpha 2A)- and h(alpha 2C)-ARs, piribedi l antagonized induction of [S-35]guanosine-5'-O-(3-thio)triphosphate (GTP g ammaS) binding by norepinephrine (NE) with pK(b) values of 6.5 and 6.9, res pectively. Furthermore, Schild analysis of the actions of piribedil at h(al pha 2A)-ARs indicated competitive antagonism, yielding a pA(2) of 6.5. At a porcine alpha (2A)-AR-Gi1 alpha -Cys351C (wild-type) fusion protein, pirib edil competitively abolished (pA(2), = 6.5) GTPase activity induced by epin ephrine. However, at a alpha (2A)-AR-Gi1 alpha -Cys3511 (mutant) fusion pro tein of amplified sensitivity, although still acting as a competitive antag onist (pA(2) = 6.2) of epinephrine, piribedil itself manifested weak partia l agonist properties. Similarly, piribedil weakly induced mitogen-activated protein kinase phosphorylation via wild-type h(alpha 2A)-ARs, although att enuating its phosphorylation by NE. As demonstrated by functional [S-35]GTP gammaS autoradiography in rats, piribedil antagonized activation by NE of alpha (2)-ARs in cortex, amygdala, and septum. Antagonist properties were a lso expressed in a dose-dependent enhancement of the firing rate of adrener gic neurons in locus ceruleus (0.125-4.0 mg/kg i.v.). Furthermore, piribedi l (2.5-4.0 mg/kg s.c.) accelerated hippocampal NE synthesis, elevated dialy sis levels of NE in hippocampus and frontal cortex, and blocked hypnotic-se dative properties of the alpha (2)-AR agonist xylazine. Finally, piribedil showed only modest affinity for rat alpha (1)-ARs (5.9) and weakly antagoni zed NE-induced activation of phospholipase C via h(alpha 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 m ay, thus, contribute to its clinical antiparkinsonian profile.