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

• Published in: Neuropharmacology 2000-04, Vol.39 (7), p.1197-1210
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - metabolism; Animals; Antipsychotic Agents - pharmacology; Benzazepines - pharmacology; Biogenic Amines - metabolism; Brain Chemistry - drug effects; Cells, Cultured; CHO Cells; Cricetinae; Dopamine Agonists - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists - metabolism; Electrophysiology; Humans; Male; Membranes - drug effects; Membranes - 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; Serotonin Receptor Agonists - pharmacology; Spiperone - metabolism; Tetrahydronaphthalenes - metabolism; Thiophenes - metabolism
• ISSN: 0028-3908

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.