Abstract
Compared with cloned, human (h)D2 receptors (pKi = 6.9), the antiparkinsonian agent piribedil showed comparable affinity for hα2A- (7.1) and hα2C- (7.2) adrenoceptors (ARs), whereas its affinity for hα2B-ARs was less marked (6.5). At hα2A- and hα2C-ARs, piribedil antagonized induction of [35S]guanosine-5′-O-(3-thio)triphosphate (GTPγS) binding by norepinephrine (NE) with pKb values of 6.5 and 6.9, respectively. Furthermore, Schild analysis of the actions of piribedil at hα2A-ARs indicated competitive antagonism, yielding a pA2 of 6.5. At a porcine α2A-AR-Gi1α-Cys351C (wild-type) fusion protein, piribedil competitively abolished (pA2 = 6.5) GTPase activity induced by epinephrine. However, at a α2A-AR-Gi1α-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 hα2A-ARs, although attenuating its phosphorylation by NE. As demonstrated by functional [35S]GTPγS autoradiography in rats, piribedil antagonized activation by NE of α2-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 α2-AR agonist xylazine. Finally, piribedil showed only modest affinity for rat α1-ARs (5.9) and weakly antagonized NE-induced activation of phospholipase C via hα1A-ARs (pKb = 5.6). In conclusion, piribedil displays essentially antagonist properties at cloned, human and cerebral, rat α2-ARs. Blockade of α2-ARs may, thus, contribute to its clinical antiparkinsonian profile.
Footnotes
-
Send reprint requests to: Dr. Mark J. Millan, Institut de Recherches Servier, Center de Recherches de Croissy, 125 chemin de Ronde, 78290 Croissy/Seine, Paris, France. E-mail:mark.millan{at}fr.netgrs.com
- Abbreviations:
- DA
- dopamine
- AR
- adrenoceptor
- NE
- norepinephrine
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- [35S]GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- CHO
- Chinese hamster ovary
- HEK
- human embryonic kidney
- GTP
- guanosine triphosphate
- MAPK
- mitogen-activated-protein kinase
- PI
- phosphatidylinositol
- CL
- confidence limits
- FCX
- frontal cortex
- LRR
- loss of righting reflex
- p
- porcine
- h
- human
- Received December 11, 2000.
- Accepted February 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics