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Journal of Psychopharmacology
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0269881107082944v1
23/1/65    most recent
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Asenapine: a novel psychopharmacologic agent with a unique human receptor signature

M. Shahid

Schering-Plough, Newhouse, Lanarkshire, UK, mohammed.shahid{at}spcorp.com

GB Walker

Schering-Plough, Newhouse, Lanarkshire, UK

SH Zorn

Pfizer Global R&D, Ann Arbor, MI, USA

Ehf Wong

Pfizer Global R&D, Ann Arbor, MI, USA

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT 5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors ({alpha}1 [8.9], {alpha}2A [8.9], {alpha}2B [9.5] and {alpha}2C [8.9]), dopamine receptors (D1 [8.9], D 2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi ≤ 5) for muscarinic receptors and was the only agent with affinity for H2 receptors. Relative to its D2 receptor affinity, asenapine had a higher affinity for 5-HT 2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT 6, {alpha}2B and D3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT 1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT 2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2 (9.1), D3 (9.1), {alpha}2A (7.3), {alpha}2B (8.3), {alpha}2C (6.8) and H1 (8.4) receptors. These functional effects differed from those of risperidone (pKB < 5 for 5-HT6) and olanzapine (pKB < 5 for 5-HT 1A and {alpha}2). Our results indicate that asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of antipsychotic drugs.

Key Words: asenapine • bipolar disorder • human receptor • affinity • schizophrenia

This version was published on January 1, 2009

Journal of Psychopharmacology, Vol. 23, No. 1, 65-73 (2009)
DOI: 10.1177/0269881107082944
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