ACP-103, a 5-Hydroxytryptamine 2A Receptor Inverse Agonist, Improves the Antipsychotic Efficacy and Side-Effect Profile of Haloperidol and Risperidone in Experimental Models

Abstract

Dopamine D 2 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 D 2 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-HT 2A receptor inverse agonist that fails to bind D 2 receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT 2A inverse agonism with low levels of D 2 antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D 2 receptor-related adverse effects. Here we show that ACP-103 1) potently inhibited head-twitching produced by the 5-HT 2A/2C receptor agonist (Ϯ)-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)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and, by contrast, 4) attenuated haloperidol-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-HT 2A 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 D 2 receptor antagonism.

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

“…Pimavanserin has also been shown to potentiate a subeffective dose of the atypical APD risperidone in acutely psychotic patients with schizophrenia, producing a more rapid onset of action than standard-dose risperidone or an equally effective dose of haloperidol, while producing fewer side effects (67). These results are consistent with evidence that pimavanserin, as well as other 5-HT 2A inverse agonists, is able to potentiate subeffective doses of atypical, but not typical, APDs in clinically relevant animal models of psychosis and cognitive impairment (68,69). The possibility that pimavanserin is effective as a monotherapy for some patients with schizophrenia is consistent with the finding that SR43469B, another 5-HT 2A inverse agonist, was reported to diminish psychotic symptoms more effectively than placebo, but slightly less so than haloperidol, in acutely psychotic patients with schizophrenia (59).…”

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

“…These atypical antipsychotic drugs with relatively high striatial D 2 RO elevate prolactin levels (Bushe et al 2008) and can induce extrapyramidal motor side effects (extrapyramidal symptoms (EPS)) at therapeutic doses (Rummel-Kluge et al 2012). Importantly, selective 5-HT 2A receptor antagonism has been shown to enhance D 2 -receptor-antagonist-mediated antipsychotic efficacy while reducing motor side effects and hyperprolactinemia in animal models (Gardell et al 2007; Wadenberg et al 1996). Moreover, antidepressant efficacy corresponding to occupancy of serotonin transporters (Meyer et al 2004b;Meyer 2007) can be enhanced by 5-HT 2A receptor antagonism with reduced sexual side effects (Aizenberg et al 1997; Marek et al 2005; Pullar et al 2000).…”

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

“…Pimavanserin (3 mg/kg) has been shown to achieve essentially 100% 5-HT 2A receptor occupancy (Vanover et al, 2006) and potentiated the ability of sub-effective doses of atypical APDs to reverse the NOR deficit induced by subchronic PCP (Snigdha et al, 2010). It is noteworthy that haloperidol and pimavanserin effectively block acute NMDA receptor antagonist (eg, PCP, MK-801)-induced hyperlocomotion, considered a model of psychosis (Maurel-Remy et al, 1995;Vanover et al, 2006;Gardell et al, 2007). Ritanserin, another 5-HT 2A inverse agonist, was able to block the ability of PCP to increase cortical 5-HT efflux (Amargós -Bosch et al, 2006).…”