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

H. C. Akunne, K. T. Zoski, M. D. Davis, L. W. Cooke, L. T. Meltzer, S. Z. Whetzel, Y. H. Shih, D. J. Wustrow, L. D. Wise, R. G. MacKenzie, L. M. Georgic, T. G. Heffner, T. A. Pugsley

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Abstract

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 D4.2 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.

Original languageEnglish (US)
Pages (from-to)1197-1210
Number of pages14
JournalNeuropharmacology
Volume39
Issue number7
DOIs
StatePublished - Jun 1 2000

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Keywords

  • Agonist
  • Antipsychotic
  • Autoreceptor
  • DA receptors
  • Haloperidol
  • Thymidine uptake

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Akunne, H. C., Zoski, K. T., Davis, M. D., Cooke, L. W., Meltzer, L. T., Whetzel, S. Z., Shih, Y. H., Wustrow, D. J., Wise, L. D., MacKenzie, R. G., Georgic, L. M., Heffner, T. G., & Pugsley, T. A. (2000). PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects. Neuropharmacology, 39(7), 1197-1210. https://doi.org/10.1016/S0028-3908(99)00224-5