title: 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.affiliation: Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, USA. hyacinth.akunne@wl.com
authors.forename: H C
authors.initials: HC
authors.lastname: Akunne
authors.forename: K T
authors.initials: KT
authors.lastname: Zoski
authors.forename: M D
authors.initials: MD
authors.lastname: Davis
authors.forename: L W
authors.initials: LW
authors.lastname: Cooke
authors.forename: L T
authors.initials: LT
authors.lastname: Meltzer
authors.forename: S Z
authors.initials: SZ
authors.lastname: Whetzel
authors.forename: Y H
authors.initials: YH
authors.lastname: Shih
authors.forename: D J
authors.initials: DJ
authors.lastname: Wustrow
authors.forename: L D
authors.initials: LD
authors.lastname: Wise
authors.forename: R G
authors.initials: RG
authors.lastname: MacKenzie
authors.forename: L M
authors.initials: LM
authors.lastname: Georgic
authors.forename: T G
authors.initials: TG
authors.lastname: Heffner
authors.forename: T A
authors.initials: TA
authors.lastname: Pugsley
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013134:Spiperone / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D013876:Thiophenes / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D001679:Biogenic Amines; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; C111318:PD 158771; D010879:Piperazines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C047508:rotigotine