PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT1A agonist actions. I. Neurochemical effects
| Autor: | Kim Zoski, Lawrence D. Wise, Steven Z. Whetzel, Lynn M. Georgic, Robert G. MacKenzie, Y H Shih, L. W. Cooke, T. A. Pugsley, Thomas G. Heffner, Leonard T. Meltzer, Michael Duff Davis, David J. Wustrow, Hyacinth Akunne |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Agonist Biogenic Amines medicine.medical_specialty Tetrahydronaphthalenes medicine.drug_class CHO Cells Thiophenes Pharmacology Partial agonist Piperazines Cellular and Molecular Neuroscience Quinpirole Dopamine Cricetinae Internal medicine medicine Animals Humans Rats Long-Evans Receptor Cells Cultured Brain Chemistry 8-Hydroxy-2-(di-n-propylamino)tetralin Membranes Receptors Dopamine D2 Chemistry Receptors Dopamine D3 Benzazepines Rats Serotonin Receptor Agonists Electrophysiology Neostriatum Pyrimidines Endocrinology Mechanism of action Spiperone Receptors Serotonin Dopamine Agonists Autoreceptor Dopamine Antagonists Serotonin medicine.symptom Receptors Serotonin 5-HT1 Antipsychotic Agents medicine.drug |
| Zdroj: | Neuropharmacology. 39:1197-1210 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/s0028-3908(99)00224-5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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