Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.

Introduction: There is a major societal need for analgesics with less tolerance, dependence, and abuse liability. Preclinical rodent studies suggest that bifunctional ligands with both mu (MOPr) and delta (DOPr) opioid peptide receptor activity may produce analgesia with reduced tolerance and other side effects. This study explores the structure-activity relationships (SAR) of our previously reported MOPr/DOPr lead, benzylideneoxymorphone (BOM) with C7-methylene-substituted analogs. Methods: Analogs were synthesized and tested in vitro for opioid receptor binding and efficacy. One compound, nitro-BOM (NBOM, 12) was evaluated for antinociceptive effects in the warm water tail withdrawal assay in C57BL/6 mice. Acute and chronic antinociception was determined, as was toxicologic effects on chronic administration. Molecular modeling experiments were performed using the Site Identification by Ligand Competitive Saturation (SILCS) method. Results: NBOM was found to be a potent MOPr agonist/DOPr partial agonist that produces high-efficacy antinociception. Antinociceptive tolerance was observed, as was weight loss; this toxicity was only observed with NBOM and not with BOM. Modeling supports the hypothesis that the increased MOPr efficacy of NBOM is due to the substituted benzylidene ring occupying a nonpolar region within the MOPr agonist state. Discussion: Though antinociceptive tolerance and non-specific toxicity was observed on repeated administration, NBOM provides an important new tool for understanding MOPr/DOPr pharmacology.

Factors associated with food intake, nutritional status, and function among nursing home residents with dementia.

Declined food intake is prevalent among long-term care (LTC) residents with dementia and associated with deleterious health outcomes. This study explores food intake, nutritional status, and function and its associated factors in LTC residents with dementia. Data from 82 LTC residents with dementia were used in this secondary analysis. The majority of residents were either malnourished or at risk of being malnourished and demonstrated a worse appetite than previously described in the literature. Comorbid illness, depressed mood, and appetite were associated with 37.1% of the variance in food intake over 30 days. Dementia level and appetite were associated with 22.2% of the variance in nutritional status. Food intake and nutritional status were associated with 29.1% of the variance in function. This study also highlights a new demographic that may require extra assistance in combating declined food intake: LTC residents with dementia who reside in a facility that follows restrictive food practices such as a kosher diet. The potential reversibility of factors associated with food intake and nutritional status provides opportunities for intervention.