Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907.
The present study determined the biochemical and pharmacological effects of PD 128907 [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol], a dopamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128907 displaced [3H]spiperone in a biphasic fashion which fit best to a two-site model, generating Ki values of 20 and 6964 nM for the high- and low-affinity sites for the D2L receptors and 1.43 and 413 nM for the corresponding sites for the D3 receptors. Addition of sodium and the GTP analog Gpp(NH)p to both the D2L and D3 caused a modest reduction in the affinity of the compound suggestive of an agonist type action. In agonist binding ([3H]N-0437), PD 128907 exhibited an 18-fold selectivity for D3 versus D2L, a selectivity similar to that found with antagonist binding to the high-affinity sites. PD 128907 exhibited only weak affinity for D4.2 receptors (Ki = 169 nM). No significant affinity for a variety of other receptors was observed. PD 128907 stimulated cell division (measured by [3H]thymidine uptake) in CHO p-5 cells transfected with either D2L or D3 receptors exhibiting about a 6.3-fold greater potency in activating D3 as compared to D2L receptors. In vivo the compound was active in reducing DA synthesis both in normal and gamma-butyrolactone (GBL) treated rats; in the GBL model, the decrease was greater in the higher D3-expressing mesolimbic region as compared with striatum which has a lower expression of D3 receptors. PD 128907 decreased DA release (as measured by brain microdialysis) both in rat striatum, nucleus accumbens and medial frontal cortex, as well as in monkey putamen. Behaviorally PD 128907 decreased spontaneous locomotor activity (LMA) in rats at low doses, whereas at higher doses stimulatory effects were observed. PD 128907 at high doses reversed the reserpine-induced decrease in LMA and induced stereotypy in combination with the D1 agonist SKF 38393 indicating postsynaptic DA agonist actions. It is unclear which of the subtypes of DA receptors might be mediating the pharmacological effects of PD 128907. However, the present findings indicating that PD 128907 shows a preference for DA D3 over D2L and D4.2 receptors indicates that its action at low doses may be due to interaction with D3 receptors and at higher doses, with both D2 and D3 receptors.
Department of Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, Michigan, USA.
T A
TA
Pugsley
M D
MD
Davis
H C
HC
Akunne
R G
RG
MacKenzie
Y H
YH
Shih
G
G
Damsma
H
H
Wikstrom
S Z
SZ
Whetzel
L M
LM
Georgic
L W
LW
Cooke
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D010078:Oxazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012453:Saimiri; D013134:Spiperone / Q000378:metabolism
D001578:Benzopyrans; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D013134:Spiperone