A cellular perspective of bias at G protein-coupled receptors.

G protein-coupled receptors (GPCRs) modulate cell function over short- and long-term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur, and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.

Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show in Vitro Kappa and Mu Opioid Receptor Agonism.

The dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold was originally developed in the production of selective delta opioid receptor (DOR) antagonists. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline core of this classic opioid scaffold introduced kappa opioid receptor (KOR) agonism. Further modification of this pendant resulted in retention of KOR agonism and the addition of mu opioid receptor (MOR) partial agonism, a bifunctional profile with potential to be used in the treatment of cocaine addiction.

Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic µ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability.

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. Although these attributes are promising, these analogues exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, a structure-activity relationship (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 analogues were discovered. These analogues (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retained their DOR-antagonist properties, and showed a 10-fold improvement in metabolic stability.

Dual Pharmacophores Explored via Structure-Activity Relationship (SAR) Matrix: Insights into Potent, Bifunctional Opioid Ligand Design.

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 to 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 two-dimensional structure-activity relationship 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.

Synthesis and Pharmacological Evaluation of Novel C-8 Substituted Tetrahydroquinolines as Balanced-Affinity Mu/Delta Opioid Ligands for the Treatment of Pain.

The use of opioids for the treatment of pain, while largely effective, is limited by detrimental side effects including analgesic tolerance, physical dependence, and euphoria, which may lead to opioid abuse. Studies have shown that compounds with a µ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist profile reduce or eliminate some of these side effects including the development of tolerance and dependence. Herein we report the synthesis and pharmacological evaluation of a series of tetrahydroquinoline-based peptidomimetics with substitutions at the C-8 position. Relative to our lead peptidomimetic with no C-8 substitution, this series affords an increase in DOR affinity and provides greater balance in MOR and DOR binding affinities. Moreover, compounds with carbonyl moieties at C-8 display the desired MOR agonist/DOR antagonist profile whereas alkyl substitutions elicit modest DOR agonism. Several compounds in this series produce a robust antinociceptive effect in vivo and show antinociceptive activity for greater than 2 h after intraperitoneal administration in mice.

Evaluation of radiation exposure with Tru-Align intraoral rectangular collimation system using OSL dosimeters.

A pilot study to compare radiation exposure with the Tru-Align rectangular collimation system to round collimation exposures was undertaken. Radiation exposure at various points within the cross sections of the collimators and entrance, intraoral and exit dose measurements were measured using InLight OSL dosimeters. Overall dose reduction with the use of the rectangular collimation system was estimated by taking into account the ratios of collimator openings and the average radiation exposure at the measurement points. Use of the Tru-Align system resulted in an average radiation exposure within the perimeter of the projected outline of the rectangular collimator of 36.1 mR, compared to 148.5 mR with the round collimator. Our calculations indicate a dose reduction by a factor of approximately 3.2 in the case of the Tru-Align system compared to round collimation. The Tru-Align system was easy to use, but in some situations failed to allow Xray coverage of the entire surface of the image receptor, leading to cone cuts.

Fetal radiation dose during gestation estimated on an anthropomorphic phantom for three generations of CT scanners.

OBJECTIVE: The purpose of this study is to determine fetal dose during four different stages of pregnancy for both pulmonary CT angiogram and abdominal and pelvic CT examination on 4-, 16-, and 64-MDCT scanners measured in an anthropomorphic phantom simulating a pregnant patient. MATERIALS AND METHODS: Pulmonary angiograms and abdominal and pelvic studies were performed on a phantom on 4-, 16-, and 64-MDCT scanners. Fetal positioning and mean fetal depth were determined using data from ultrasound examinations of a large cohort of patients. Scans were performed for early pregnancy and for 10, 18, and 36 weeks. Gestational age, fetal dose, and entrance skin exposure were measured. RESULTS: When constant parameters were used for pulmonary CT angiograms, the fetal radiation dose was not significantly associated with gestational age. For abdominal examinations, the 64-MDCT scanner imparted a 20% higher dose during the third trimester than did the other scanners. When scanning parameters were kept constant between machines, gestational age and fetal dose were not significantly different. However, when the manufacturer-recommended protocols for pregnant patients were used, the dose was significantly higher in the third trimester on the 64-MDCT scanner. CONCLUSION: 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.