Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity.

Herein, we report the structure-activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D4 receptor with IC50 = 130 nM and K i = 36 nM and shows no activity against the other dopamine receptors tested (>20 µM against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.

Spiroaminal Model Systems of the Marineosins with Final Step Pyrrole Incorporation.

In this Letter, we describe a short, 6-step enantioselective route to spiroaminal lactam model systems reminiscent of marineosins A and B has been developed starting from either (R)- or (S)-hydroxysuccinic acid, respectively, in ~9% overall yield. This route enables late stage incorporation of the pyrrole ring at C5 via nucleophilic displacement of an iminium triflate salt.

Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic Pyrrole and an Advanced, Functionalized Spiroaminal Model.

Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core 4 of marineosin A in 5.1% overall yield from (S)-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is then subjected to Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) to afford macrocycle 4. A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system 8 via an acid-mediated hydroxyketoamide cyclization strategy.

Effect of concord grape juice on chemotherapy-induced nausea and vomiting: results of a pilot study.

PURPOSE/OBJECTIVES: To determine the feasibility of administering a flavonoid-rich adjunctive treatment (Concord grape juice) for the management of chemotherapy-induced nausea and vomiting (CINV); to evaluate the usefulness of existing measures for assessing CINV frequency and severity, quality of life, control over life events, and psychological state; to identify any actual or potential adverse events associated with frequent grape juice intake; and to provide preliminary data concerning the effect of Concord grape juice on CINV, quality of life, perceived control over life events, and psychological state. DESIGN: Double-blind, randomized clinical trial. SETTING: A cancer center in an academic health science center in the northeastern United States. SAMPLE: 77 adult patients with cancer receiving moderately or highly emetogenic chemotherapy agents. METHODS: Participants drank 4 oz. of grape juice or placebo prior to meals for one week following each of four chemotherapy treatment cycles. They recorded frequency, duration, and distress of nausea, vomiting, and retching daily, beginning the evening of chemotherapy administration and continuing for seven days. Data were analyzed with generalized estimating equations methodology to model differences between groups over time. MAIN RESEARCH VARIABLES: Nausea and vomiting frequency, duration, and distress; quality of life; control over decision making; and psychological state. FINDINGS: Nausea and vomiting frequency, duration, and distress were lower for experimental group members, although a high attrition rate (50%) resulted in insufficient power to detect statistically significant differences over time. Greater levels of anxiety, depression, and hostility at baseline were related to nausea and vomiting, quality of life, and perceived control over decision making. CONCLUSIONS: The effect of grape juice flavonoids on CINV should be investigated further with a larger sample to determine whether preliminary findings are supported. Alterations to the study protocol will be necessary to decrease attrition. IMPLICATIONS FOR NURSING: Flavonoid-rich fruits and vegetables may provide additional protection against CINV. If the compounds work, they would offer a low-cost, readily available adjunctive treatment for the management of CINV.

Meeting Magnet research evidence-based practice expectations through hospital-based research centers.

Hospital-based nursing research centers can create the structures and processes needed to promote and sustain research and evidence-based practice (EBP) and assist in the monitoring of care delivery outcomes. At the University of Rochester Medical Center, New York, a highly successful nursing research center has succeeded in creating a Magnet environment that incorporates research and EBP into strategic planning, individual employee performance review, and organizational processes. Support of a hospital-based research center can provide the foundation for an infrastructure that supports achievement of Magnet designation research and EBP criteria. The costs pertain primarily to the staff required to develop and manage the center and the educational programs offered through it. Based on the experience at this center, administrators should plan 3-5 years before significant impact is seen in terms of numbers of consultations performed and tangible increases in staff and leadership participation in research and EBP initiatives.