Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

Abstract

Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structureactivity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H 1 receptors may significantly advance schizophrenia therapy.

Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

“…approximately 30–50 % at 100 μM) [6,8]. Since hyperlipidemia and metabolic syndrome are known side effects of this family of drugs [19], we compared a set of related compounds for ability to inhibit FA transport by comparison with Grassofermata (Table 1). At best, the compounds had a modest effect in preventing PA-mediated lipid accumulation and nuclear fragmentation when provided at relatively high doses (50 and 100 μM).…”

Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats

“…These data suggested that weight gain or obesity might not be a single crucial factor for onset of metabolic side-effects, such as insulin resistance anddyslipidemia 42 . Notably, previous studies reported that OLZ and CLZ had a similar antagonist activity at histaminergic subtype 1 (H 1 ) receptors, and the affinity for H 1 receptors played a key role in drug-induced weight gain 53, 54 , however, metabolic side-effects could be associated with their plasma concentrations 55 . Further studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.…”

Effect of Atypical Antipsychotics on Fetal Growth: Is the Placenta Involved?

“…In addition, they also target the serotonin receptor subtype 2A (5HT 2A ) [19] which may help to reduce the negative side-effects associated with typical antipsychotics [19, 20]. It is important to note that the proper correlation between the ratio of the clinical dosage and D 2 receptor affinity necessary to treat the symptoms of conditions such as schizophrenia has not been completely established [21]. …”