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

BACKGROUND AND PURPOSE:

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).

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 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 AND IMPLICATIONS:

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: A Newman-Tancredi, M-B Assié, J-C Martel, C Cosi, L Bruins Slot, C Palmier, I Rauly-Lestienne, F Colpaert, B Vacher, D Cussac
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 151 Issue 2 Pg. 237-52 (May 2007) ISSN: 0007-1188 [Print] England
• PMID: 17375087 (Publication Type: Journal Article)

Chemical References

• Antipsychotic Agents
• Benzofurans
• Benzylamines
• Cyclopentanes
• Dopamine Agonists
• Dopamine Antagonists
• N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)benzylamine
• Receptors, Dopamine
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A

Topics

• Animals
• Antipsychotic Agents (chemistry, metabolism, pharmacology)
• Benzofurans (chemistry, metabolism, pharmacology)
• Benzylamines (chemistry, metabolism, pharmacology)
• Binding, Competitive (drug effects)
• CHO Cells
• COS Cells
• Cell Line
• Chlorocebus aethiops
• Cricetinae
• Cricetulus
• Cyclopentanes (chemistry, metabolism, pharmacology)
• Dopamine Agonists (chemistry, metabolism, pharmacology)
• Dopamine Antagonists (chemistry, metabolism, pharmacology)
• Dose-Response Relationship, Drug
• HeLa Cells
• Humans
• Male
• Molecular Structure
• Phosphorylation (drug effects)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Receptors, Dopamine (metabolism)
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Receptor Agonists (chemistry, metabolism, pharmacology)
• Spodoptera
• Swine