PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5-HT(1A) 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 (sigma) -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.

• Authors: 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
• Journal: Neuropharmacology (Neuropharmacology) Vol. 39 Issue 7 Pg. 1197-210 (Apr 27 2000) ISSN: 0028-3908 [Print] England
• PMID: 10760362 (Publication Type: Journal Article)

Chemical References

• Antipsychotic Agents
• Benzazepines
• Biogenic Amines
• DRD3 protein, human
• Dopamine Agonists
• Dopamine Antagonists
• Drd3 protein, rat
• PD 158771
• Piperazines
• Pyrimidines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists
• Tetrahydronaphthalenes
• Thiophenes
• Spiperone
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• rotigotine

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (metabolism)
• Animals
• Antipsychotic Agents (pharmacology)
• Benzazepines (pharmacology)
• Biogenic Amines (metabolism)
• Brain Chemistry (drug effects)
• CHO Cells
• Cells, Cultured
• Cricetinae
• Dopamine Agonists (metabolism, pharmacology)
• Dopamine Antagonists (metabolism)
• Electrophysiology
• Humans
• Male
• Membranes (drug effects, metabolism)
• Neostriatum (metabolism)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Long-Evans
• Receptors, Dopamine D2 (agonists)
• Receptors, Dopamine D3
• Receptors, Serotonin (drug effects)
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists (metabolism, pharmacology)
• Spiperone (metabolism)
• Tetrahydronaphthalenes (metabolism)
• Thiophenes (metabolism)