Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Abstract

Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…Its target optimization included D 2 partial agonism with low intrinsic activity, 5-HT 1A partial agonism, and antagonism at 5-HT 2A , a 1B -and a 2C -adrenergic receptors (Maeda et al, 2014), supporting a favorable antipsychotic profile with low EPS risk and potential to treat core symptoms in schizophrenia, including cognitive deficits (Arnt and Skarsfeldt, 1998;Drouin et al, 2002;Marcus et al, 2010;Newman-Tancredi and Kleven, 2011;Sallinen et al, 2013).…”

“…Some compounds also affect a variety of other monoamine receptors, such as 5-HT 1A/6/7 receptors, a 2 -adrenoceptors, and histamine and muscarinic receptors. The broad target effects are aimed at either improving efficacy (e.g., potential effects on affective symptoms or cognitive deficits) or mitigating adverse effects related to the central nervous system (CNS), such as extrapyramidal symptoms (EPS), or to the endocrine system, such as hyperprolactinemia (Arnt and Skarsfeldt, 1998;Roth et al, 2004;Arnt et al, 2008;NewmanTancredi, 2010;Newman-Tancredi and Kleven, 2011).…”

Serotonin-1A Receptors and Cognitive Enhancement in Schizophrenia: Role for Brain Energy Metabolism

“…summarizes the mode of actions (agonism or antagonism) and specific compounds related to the above-mentioned 5-HT receptor subtypes. Among them, 5-HT 1A receptor stimulation is currently considered as the most promising approach (Llado-Pelfort et al 2011, Newman-Tancredi and Kleven 2011, Newman-Tancredi and Albert in press, Sumiyoshi C. et al 2006, Sumiyoshi T. et al 2007a, Sumiyoshi T. et al 2000, Sumiyoshi T. et al 2007b, Sumiyoshi T. et al 2001a, Sumiyoshi T. et al 2001b), as discussed in the next section. This is followed by 5-HT 2A antagonism, as elicited by certain (although not satisfactory) efficacy of a series of AAPDs whose principal pharmacologic feature is blockade of 5-HT 2A receptors (Meltzer et al 1989, Meltzer and Massey 2011, Stockmeier et al 1993, Sumiyoshi T. et al 1995.…”

“…Buspirone outperformed placebo in improving the performance on a measure of attention/speeded motor performance (effect size = 0.32), indicating an advantage for cognitive abilities regulated by prefrontal cortex, as in the case of tandospirone. Evidence from these proof-ofconcept studies has prompted the recent endeavor to develop cognition-enhancing drugs with 5-HT 1A agonist actions (Depoortere et al 2010, Llado-Pelfort et al 2010, Llado-Pelfort et al 2011, Newman-Tancredi 2010, Newman-Tancredi and Kleven 2011). Some of the compounds so far synthesized in this line are shown in Fig 5. www.intechopen.com Support for this therapeutic strategy comes from animal data suggesting 5-HT 1A partial agonists (e.g.…”

“…Specifically, we will focus on several psychotropic/antipsychotic compounds stimulating 5-HT 1A receptors, considered as one of the most promising candidates for cognitive enhancers (Meltzer et al 2011, Newman-Tancredi andKleven 2011, Newman-Tancredi andAlbert in press). A hypothesis is presented on the relationship between cognition and lactate that provides an important energy substrate and reflects neural activity in the brain.…”