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F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile. PDF

Newman-Tancredi A, Assié MB, Martel JC, Cosi C, Slot LB, Palmier C, Rauly-Lestienne I, Colpaert F, Vacher B, Cussac D.
Br J Pharmacol. 2007 May;151(2):237-52. Epub 2007 Mar 20.

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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 (pKb values 9.19, 8.29 and 8.74 in [35S]GTPgammaS 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 [(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 [35S]GTP gamma S binding at hD4 (29%, 8.15) and h5-HT1D receptors (35%, 7.68). In [35S]GTPgammaS 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).