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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.

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.

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.

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Opioid analgesics exert their therapeutic and unwanted effects by activation of the mu‐opioid receptor (MOR). Repeated administration of opioid analgesics and subsequent chronic MOR activation promotes opioid tolerance and physical dependence. It has been proposed that activation of MOR with concurrent antagonism of the delta‐opioid receptor (DOR) can attenuate the development of opioid tolerance and dependence. To further investigate the utilization of concurrent MOR agonism and DOR antagonism we designed, synthesized, and characterized a library of “peptidomimetics” that have elements of opioid peptides vital for activity but retain small molecule‐like features necessary for blood‐brain‐barrier penetration. Compounds were evaluated in membrane preparations of cloned cell lines expressing either MOR, DOR, or kappa‐opioid receptors (KOR). [35S]‐GTPγS binding to measure G protein‐coupled activation was used. Full agonists at each opioid receptor (DAMGO, DPDPE, and U69,593, respectively) were employed as standards. Maximum binding and potency (EC50) values were determined from concentration‐effect curves. To measure affinity (Ki) values, competition binding using [3H]‐diprenorphine was performed. Peptidomimetics that demonstrated promising bi‐functional activity were tested for antinociceptive activity in vivo. Compared to repeated morphine‐treated mice, repeated peptidomimetic treated mice developed less analgesic tolerance or physical dependence. Analysis of in vitro and in vivo data has permitted structure‐activity relationships to guide further chemical synthesis and the discovery of opioid analgesics that may have improved clinical utility.Support or Funding InformationSupported by DA‐03910This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.