title: F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile.
abstract: OBJECTIVE
  Combining 5-HT(1A) receptor activation with dopamine D(2)/D(3) receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe the in vitro profile of F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine).
  
  
  METHODS
  F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.
  
  
  RESULTS
  Affinities (receptor and pK(i) values) of F15063 were: rD(2) 9.38; hD(2L) 9.44; hD(2S) 9.25; hD(3) 8.95; hD(4) 8.81; h5-HT(1A) 8.37. F15063 had little affinity (40-fold lower than D(2)) at other targets. F15063 antagonised dopamine-activated G-protein activation at hD(2), rD(2) and hD(3) receptors with potency (pK (b) values 9.19, 8.29 and 8.74 in [(35)S]GTP gamma S binding experiments) similar to haloperidol. F15063 did not exhibit any hD(2) receptor agonism, even in tests of ERK1/2 phosphorylation and G-protein activation in cells with high receptor expression. In contrast, like (+/-)8-OH-DPAT, F15063 efficaciously activated h5-HT(1A) (E(max) 70%, pEC(50) 7.57) and r5-HT(1A) receptors (52%, 7.95) in tests of [(35)S]GTP gamma S binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [(35)S]GTP gamma S binding at hD(4) (29%, 8.15) and h5-HT(1D) receptors (35%, 7.68). In [(35)S]GTP gamma S autoradiography, F15063 activated G-proteins in hippocampus, cortex and septum (regions enriched in 5-HT(1A) receptors), but antagonised quinelorane-induced activation of D(2)/D(3) receptors in striatum.
  
  
  CONCLUSIONS
  F15063 antagonised dopamine D(2)/D(3) receptors, a property underlying its antipsychotic-like activity, whereas activation of 5-HT(1A) and D(4) receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).
authors: Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France. adrian.newman.tancredi@pierre-fabre.com
authors: A
authors: A
authors: Newman-Tancredi
authors: M-B
authors: MB
authors: Assié
authors: J-C
authors: JC
authors: Martel
authors: C
authors: C
authors: Cosi
authors: L Bruins
authors: LB
authors: Slot
authors: C
authors: C
authors: Palmier
authors: I
authors: I
authors: Rauly-Lestienne
authors: F
authors: F
authors: Colpaert
authors: B
authors: B
authors: Vacher
authors: D
authors: D
authors: Cussac
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018411:Spodoptera; D013552:Swine
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; D001596:Benzylamines; D003517:Cyclopentanes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C518313:N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)benzylamine; D011954:Receptors, Dopamine; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A