No abstract

We have previously reported a series of μ-opioid receptor (MOR) agonist/ δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in mice, and do not produce dependence. While these attributes are promising, these analogs exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, an SAR campaign was pursued to improve their metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a monocyclic benzylic core system. By eliminating one of the rings in this scaffold and exploring the SAR of this new core, two promising analogs were discovered. These analogs (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retain their DOR antagonist properties, and showed a 10-fold improvement in metabolic stability.

Short-acting μ-opioid receptor (MOR) agonists have long been used for the treatment of severe, breakthrough pain. However, selective MOR agonists including fentanyl and morphine derivatives are limited clinically due high risks of dependence, tolerance, and respiratory depression. We recently reported the development of a long-acting, bifunctional MOR agonist/δ-opioid receptor (DOR) antagonist analgesic devoid of tolerance or dependence in mice (AAH8, henceforth referred to as 2B). To address the need for short-acting treatments for breakthrough pain, we present a series of novel, short-acting, high-potency MOR agonist/DOR antagonist ligands with antinociceptive activity in vivo. In this study, we utilized a 2D structure-activity relationship (SAR) matrix to identify pharmacological trends attributable to combinations of two key pharmacophore elements within the chemotype. This work enhances our ability to modulate efficacy at MOR and DOR, accessing a variety of bifunctional profiles while maintaining high affinity and potency at both receptors.

The 64-MDCT scanner is the most dose-efficient machine when the fetus is outside the direct scan volume, as in the case of pulmonary angiograms. For abdominal examinations, the 64-MDCT scanner imparted the highest fetal dose. This finding is attributable to the increased tube current used to penetrate the larger amount of soft tissue in late pregnancy. Abdominal shielding may reduce fetal dose without affecting diagnostic ability.