TY - JOUR T1 - ACP-103, a 5-Hydroxytryptamine 2A Receptor Inverse Agonist, Improves the Antipsychotic Efficacy and Side-Effect Profile of Haloperidol and Risperidone in Experimental Models JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 862 LP - 870 DO - 10.1124/jpet.107.121715 VL - 322 IS - 2 AU - Luis R. Gardell AU - Kimberly E. Vanover AU - Linda Pounds AU - Robert W. Johnson AU - Richard Barido AU - Gary T. Anderson AU - Isaac Veinbergs AU - Agnete Dyssegaard AU - Per Brunmark AU - Ali Tabatabaei AU - Robert E. Davis AU - Mark R. Brann AU - Uli Hacksell AU - Douglas W. Bonhaus Y1 - 2007/08/01 UR - http://jpet.aspetjournals.org/content/322/2/862.abstract N2 - Dopamine D2 receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling, and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. Whereas these agents are D2 receptor antagonists, they are also potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonists, a feature that may explain their improved efficacy and tolerability. Recently, we reported that N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel selective 5-HT2A receptor inverse agonist that fails to bind D2 receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT2A inverse agonism with low levels of D2 antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D2 receptor-related adverse effects. Here we show that ACP-103 1) potently inhibited head-twitching produced by the 5-HT2A/2C receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine, 2) increased the potency of haloperidol against amphetamine-induced hyperactivity, 3) interacted synergistically with haloperidol or risperidone to suppress hyperactivity induced by the N-methyl-d-aspartate receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and, by contrast, 4) attenuated haloperido-l- or risperidone-induced prolactinemia. ACP-103 also attenuated catalepsy produced by haloperidol or risperidone. However, the doses that were required for this effect were higher than would be expected for a 5-HT2A receptor-mediated mechanism. These data indicate that utilizing ACP-103 as an adjunctive therapy to currently used APDs may result in enhanced antipsychotic efficacy while reducing adverse effects including those attributable to D2 receptor antagonism. The American Society for Pharmacology and Experimental Therapeutics ER -