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- Title
F15063, a potential antipsychotic with D<sub>2</sub>/D<sub>3</sub> antagonist, 5-HT<sub>1A</sub> agonist and D<sub>4</sub> partial agonist properties: (I) in vitro receptor affinity and efficacy profile.
- Authors
Newman-Tancredi, A.; Assié, M.-B.; Martel, J.-C.; Cosi, C.; Slot, L. Bruins; Palmier, C.; Rauly-Lestienne, I.; Colpaert, F.; Vacher, B.; Cussac, D.
- Abstract
Background and purpose:Combining 5-HT1A receptor activation with dopamine D2/D3 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).Experimental approach:F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.Key results:Affinities (receptor and pKi values) of F15063 were: rD2 9.38; hD2L 9.44; hD2S 9.25; hD3 8.95; hD4 8.81; h5-HT1A 8.37. F15063 had little affinity (40-fold lower than D2) at other targets. F15063 antagonised dopamine-activated G-protein activation at hD2, rD2 and hD3 receptors with potency (pK b values 9.19, 8.29 and 8.74 in [35S]GTPγS binding experiments) similar to haloperidol. F15063 did not exhibit any hD2 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-HT1A (Emax 70%, pEC50 7.57) and r5-HT1A receptors (52%, 7.95) in tests of [35S]GTPγS binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [35S]GTPγS binding at hD4 (29%, 8.15) and h5-HT1D receptors (35%, 7.68). In [35S]GTPγS autoradiography, F15063 activated G-proteins in hippocampus, cortex and septum (regions enriched in 5-HT1A receptors), but antagonised quinelorane-induced activation of D2/D3 receptors in striatum.Conclusions and implications:F15063 antagonised dopamine D2/D3 receptors, a property underlying its antipsychotic-like activity, whereas activation of 5-HT1A and D4 receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).British Journal of Pharmacology (2007) 151, 237–252. doi:10.1038/sj.bjp.0707158; published online 20 March 2007
- Subjects
DOPAMINE receptors; ANTIPSYCHOTIC agents; DRUG efficacy; DIAGNOSIS of schizophrenia; DRUG therapy for psychoses; MEDICAL experimentation on humans
- Publication
British Journal of Pharmacology, 2007, Vol 151, Issue 2, p237
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0707158