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

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 K i) for serotonin receptors (5-HT 1A [8.6], 5-HT 1B [8.4], 5-HT 2A [10.2], 5-HT 2B [9.8], 5-HT 2C [10.5], 5-HT 5 [8.8], 5-HT 6 [9.6] and 5-HT 7 [9.9]), adrenoceptors (α 1 [8.9], α 2A [8.9], α 2B [9.5] and α 2C [8.9]), dopamine receptors (D 1 [8.9], D 2 [8.9], D 3 [9.4] and D 4 [9.0]) and histamine receptors (H 1 [9.0] and H 2 [8.2]). It had much lower affinity (p K i ≤ 5) for muscarinic receptors and was the only agent with affinity for H 2 receptors. Relative to its D 2 receptor affinity, asenapine had a higher affinity for 5-HT 2C, 5-HT 2A, 5-HT 2B, 5-HT 7, 5-HT 6, α 2B and D 3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (p K B) at 5-HT 1A (7.4), 5-HT 1B (8.1), 5-HT 2A (9.0), 5-HT 2B (9.3), 5-HT 2C (9.0), 5-HT 6 (8.0), 5-HT 7 (8.5), D 2 (9.1), D 3 (9.1), α 2A (7.3), α 2B (8.3), α 2C (6.8) and H 1 (8.4) receptors. These functional effects differed from those of risperidone (p K B < 5 for 5-HT 6) and olanzapine (p K B < 5 for 5-HT 1A and α 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.