Evolution of schizophrenia drugs: a focus on dopaminergic systems.

Many of the drugs currently marketed for the treatment of schizophrenia are dopamine D2 receptor antagonists or partial agonists with or without mixed receptor pharmacology, and primarily treat the positive symptoms of schizophrenia. These drugs, depending on their pharmacological profile, have been categorized as typical (with low or no serotonergic component) and atypical (with a high serotonergic, 5-HT2A and 5-HT1A component) antipsychotics. Atypical antipsychotics have increased tolerability compared with typical antipsychotics, particularly against extrapyramidal side effects which are caused by D2 receptor antagonism, and an increased efficacy for the treatment of the negative symptoms associated with schizophrenia. However, over the course of treatment, adverse effects such as weight gain, metabolic disorders, QT prolongation and sexual dysfunction have been observed, and thus current research efforts are being directed to the identification of new antipsychotics that have better tolerability and efficacy against the positive and negative symptoms of schizophrenia.

A preservative-and-fluorescein interaction model for benign multipurpose solution-associated transient corneal hyperfluorescence.

PURPOSE: Multipurpose contact lens solution (MPS)/preservative-associated transient corneal hyperfluorescence has been suggested to represent corneal injury. To determine the validity of this assumption, the molecular-level interactions of common disinfectants in soft contact lens MPS and the corneal epithelium using an in vitro model were assessed. METHODS: A liposome-based model of the corneal epithelial surface was developed and used to assess the interactions of polyhexamethylene biguanide (PHMB), polyquaternium-1 (PQ-1), and fluorescein with membrane components and the effects of PHMB and PQ-1 on membrane integrity. The fluorescence anisotropy (a measure of interactions between molecules) was determined. Liposome integrity was assessed by measuring the liposome melting point temperature. RESULTS: Free fluorescein did not associate with the liposome (P>0.4). Both fluorescein-tagged PHMB and PQ-1 associated with liposomes (P<0.002 and P≤0.01, respectively); however, only PHMB induced free fluorescein association with membrane components. At physiological temperature, no significant shift in the melting point temperature was observed when liposomes were exposed to PHMB from 0 to 100 ppm (P>0.05). In contrast, exposure of >7 ppm PQ-1 disrupted the liposomes. CONCLUSIONS: Based on this study, PHMB-to-liposome bilayer interaction is nondestructive, even at concentrations 100 times higher than found in commercially available MPS products. In contrast, PQ-1-to-liposome bilayer interaction led to liposome disruption. This study presents molecular-level evidence to support that preservative-associated transient corneal hyperfluorescence is a benign transient phenomenon and its evaluation clinically may be an ambiguous strategy for determining biocompatibility and cell surface integrity.

Practical enantioselective synthesis of beta-substituted-beta-amino esters.

[reaction: see text] A practical, large-scale synthesis of a beta-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and hydrochloride salt formation in a one-pot process. The method was successfully applied toward the synthesis of a wide variety of beta-amino esters.