PD 158771, a potential antipsychotic agent with D₂/D₃ partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects

The neurochemical effects of a novel dopamine (DA) D₂-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D₃ 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 H₁ (IC₅₀ =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 [³H]thymidine uptake in CHO p-5 cells transfected with hD₃ receptors with a maximal effect of 23% relative to quinpirole. In hD₂L, the corresponding value was 60% with an EC₅₀ 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. Copyright (C) 2000 Elsevier Science Ltd.