NEUROCHEMICAL AND FUNCTIONAL-CHARACTERIZATION OF THE PREFERENTIALLY SELECTIVE DOPAMINE D3 AGONIST PD-128907

The present study determined the biochemical and pharmacological effec ts of PD 128907 opyl-2H,5H-[1]benzopyrano[4,3-6]-1,4-oxazin-9-ol], a d opamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128 907 displaced [H-3]spiperone in a biphasic fashion which fit best to a two-site model, generating K-i 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 t he GTP analog Gpp(NH)p to both the D2L and D3 caused a modest reductio n in the affinity of the compound suggestive of an agonist type action . In agonist binding ([H-3]N-0437), PD 128907 exhibited an 18-fold sel ectivity for D3 versus D2L, a selectivity similar to that found with a ntagonist binding to the high-affinity sites. PD 128907 exhibited only weak affinity for D4.2 receptors (K-i = 169 nM). No significant affin ity for a variety of other receptors was observed. PD 128907 stimulate d cell division (measured by [H-3]thymidine uptake) in CHO p-5 cells t ransfected with either D2L or D3 receptors exhibiting about a 6.3-fold greater potency in activating D3 as compared to D2L receptors. In viv o the compound was active in reducing DA synthesis both in normal and gamma-butyrolactone (GEL) treated rats; in the GEL 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 stimulat ory effects were observed. PD 128907 at high doses reversed the reserp ine-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 findin gs 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 i nteraction with D3 receptors and at higher doses, with both D2 and D3 receptors.