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
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|