PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT1A agonist actions. I. Neurochemical effects

Abstract The neurochemical effects of a novel dopamine (DA) D 2 -like and serotonin (5-HT) 5-HT 1A agonist, PD 158771, are described. PD 158771 exhibited affinities for human D 2L , D 3 and D 4.2 receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K i (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT 1A ( K i =2.6 nM) and rat hippocampal 5-HT 1A receptors ( K i =3.5 nM). Weaker affinities were observed at alpha 1-adrenergic ( K i =43 nM), histamine H 1 (IC 50 =30 nM), 5-HT 2A ( K i =24.5 nM) and sigma (σ) −1 binding sites ( K i =24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [ 3 H]thymidine uptake in CHO p-5 cells transfected with hD 3 receptors with a maximal effect of 23 % relative to quinpirole. In hD 2 L, the corresponding value was 60% with an EC 50 of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.