Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11–64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30–100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
Introduction
Prescription opioid pain reliever overdose is a major public health issue in the United States. To characterize the location of drug-related deaths, we examined fatal prescription opioid and illicit drug-related deaths reported in 12 states.
Methods
Data are from the Substance Abuse and Mental Health Services Administration's Drug Abuse Warning Network (DAWN). Medical examiners or coroners in 12 states (MA, MD, ME, NH, NM, OK, OR, RI, UT, VA, VT, WV) reported details of state-wide drug-related mortality during 2008–2010. DAWN data included location and manner of death, age, race, and drugs involved. Deaths were coded into three categories: prescription opioid-related, illicit drug-related, and cases that involved both a prescription opioid and an illicit drug.
Results
During a 3-year period, there were 14,091 opioid or illicit drug-related deaths in 12 states. More than half of the prescription opioid-related deaths in all states, except Maryland, occurred at home, rather than in public or in a health care facility. Although it was still the predominant category, lower percentages of illicit drug-related deaths occurred at home.
Conclusion
Prescription opioid overdoses have increased substantially, and the location of the person at the time of death can have important public health implications for interventions.
Practical applications
This paper highlights that bystander support can be a critical lifesaving factor in drug related deaths but may be more likely for illicit drug-related deaths than for prescription opioid-related deaths.