Introduction: Opioid analgesic prescriptions are driving trends in drug overdoses, but little is known about prescribing patterns among medical specialties. We conducted this study to examine the opioid-prescribing patterns of the medical specialties over time. Methods: IMS Health’s National Prescription Audit (NPA) estimated the annual counts of pharmaceutical prescriptions dispensed in the U.S. during 2007–2012. We grouped NPA prescriber specialty data by practice type for ease of analysis, and measured the distribution of total prescriptions and opioid prescriptions by specialty. We calculated the percentage of all prescriptions dispensed that were opioids, and evaluated changes in that rate by specialty during 2007–2012. The analysis was conducted in 2013. Results: In 2012, U.S. pharmacies and long-term care facilities dispensed 4.2 billion prescriptions, 289 million (6.8%) of which were opioids. Primary care specialties accounted for nearly half of all dispensed opioid prescriptions. The rate of opioid prescribing was highest for specialists in pain medicine (48.6%); surgery (36.5%); and physical medicine/rehabilitation (35.5%). The rate of opioid prescribing rose during 2007–2010 but leveled thereafter as most specialties reduced opioid use. The greatest percentage increase in opioid-prescribing rates during 2007–2012 occurred among physical medicine/rehabilitation specialists (+12.0%). The largest percentage drops in opioid-prescribing rates occurred in emergency medicine (−8.9%) and dentistry (−5.7%). Conclusions: The data indicate diverging trends in opioid prescribing among medical specialties in the U.S. during 2007–2012. Engaging the medical specialties individually is critical for continued improvement in the safe and effective treatment of pain.

The dopamine D3 receptor (D3R) has been implicated in substance abuse and other neuropsychiatric disorders. The high sequence homology between the D3R and D2R, especially within the orthosteric binding site (OBS) that binds dopamine, has made the development of D3R-selective compounds challenging. Here, we deconstruct into pharmacophoric elements a series of D3R-selective substituted-4-phenylpiperazine compounds, and use computational simulations and binding and activation studies to dissect the structural bases for D3R selectivity and efficacy. We find that selectivity arises from divergent interactions within a second binding pocket (SBP) separate from the OBS, whereas efficacy depends on the binding mode in the OBS. Our findings reveal structural features of the receptor that are critical to selectivity and efficacy that can be used to design highly D3R-selective ligands with targeted efficacies. These findings are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands.

N-(3-fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)-butyl)-aryl carboxamides were prepared and evaluated for binding and function at dopamine D3 (D3R) and D2 receptors (D2R). In this series, we discovered some of the most D3R selective compounds reported to date, (e.g. 8d and 8j >1000-fold D3R-selective over D2R.) In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold (e.g. D3RKi for 15b = 393 v. for 8j = 2.6 nM) resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.

One‐pot methods for the end‐group postpolymerization modification of reversible addition fragmentation chain transfer (RAFT) derived polymers were investigated. Dithioester‐terminated polymers were transformed into ω‐functionalized polymers through conjugate addition of a variety of acrylates with an intermediate thiol. These methods provide a versatile means of introducing a variety of functionalities onto the polymer terminus, while simultaneously removing the residual dithiobenzoate group. A series of functionalized polymethylmethacrylate‐b‐polystyrene (PMMA‐b‐PS) polymers were synthesized utilizing the developed methods to probe the effect of charged end groups on diblock copolymer phase separation in thin films. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 346–356, 2009