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.

In vivo effects of µ-opioid receptor agonist/δ-opioid receptor antagonist peptidomimetics following acute and repeated administration.

BACKGROUND AND PURPOSE: Agonists at µ-opioid receptors (µ-receptors) are used for pain management but produce adverse effects including tolerance, dependence and euphoria. The co-administration of a µ-receptor agonist with a δ-opioid receptor (δ-receptor) antagonist has been shown to produce antinociception with reduced development of some side effects. We characterized the effects of three µ-receptor agonist/δ-receptor antagonist peptidomimetics in vivo after acute and repeated administration to determine if this profile provides a viable alternative to traditional opioid analgesics. EXPERIMENTAL APPROACH: Three µ-receptor agonist / δ-receptor antagonist peptidomimetics, AAH8, AMB46 and AMB47, and morphine were evaluated for the development of tolerance and dependence after 5 days of twice daily treatment with escalating doses of drug (10-50 mg·kg-1 ). Antinociceptive effects were measured in the warm water tail withdrawal assay before and after repeated drug treatment. Physical dependence was evaluated by naltrexone-precipitated withdrawal jumping. The rewarding effects of AAH8 were evaluated using a conditioned place preference (CPP) assay with twice daily conditioning sessions performed for 5 days. KEY RESULTS: Morphine, AAH8, AMB47 and AMB46 all demonstrated acute antinociceptive effects, but repeated administration only produced tolerance in animals treated with morphine and AMB46. Injection of naltrexone precipitated fewer jumps in mice treated repeatedly with AAH8 as compared with morphine, AMB47 or AMB46. Conditioning with morphine, but not AAH8, produced significant CPP. CONCLUSIONS AND IMPLICATIONS: AAH8 may be a better alternative than traditional opioid analgesics, producing antinociception with less development of tolerance and dependence and may be less rewarding than morphine.

Simple structure-based approach for predicting the activity of inhibitors of beta-secretase (BACE1) associated with Alzheimer's disease.

Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) is a target of interest for treating patients with Alzheimer's disease (AD). Inhibition of BACE1 may prevent amyloid-ß (Aß) plaque formation and the development or progression of Alzheimer's disease. Known BACE1 inhibitors were analyzed using computational chemistry and cheminformatics techniques to search for quantitative structure-activity relationships (QSAR). A remarkable relationship was found with only two simple descriptors. The square of the linear correlation coefficient r(2) is 0.75. The main descriptor is the number of hydrophobic contacts in the range 4-5 Å between the atoms of the ligand and active site. The other descriptor is the number of short (<2.8 Å) hydrogen bonds. Our approach uses readily available structural data on protein-inhibitor complexes in the Protein Data Bank (PDB) but would be equally applicable to proprietary structural biology data. The findings can aid structure-based design of improved BACE-1 inhibitors. If an inhibitor has less observed activity than predicted by our correlation, the compound should be retested because the first assay may have underestimated the compound's true activity.