Asenapine: a novel psychopharmacologic agent with a unique human receptor signature

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Abstract
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 (p Ki) 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 (α1 [8.9], α2A [8.9], α2B [9.5] and α2C [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 (p Ki ≤ 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, α2B and D3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (p KB) 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), α2A (7.3), α2B (8.3), α2C (6.8) and H1 (8.4) receptors. These functional effects differed from those of risperidone (p KB < 5 for 5-HT6) and olanzapine (p KB < 5 for 5-HT 1A and α2). 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.

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