SAR Matrices Enable Discovery of Mixed Efficacy µ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore.

We previously described the development of potent µ-opioid receptor (MOR)-agonist/δ-opioid receptor (DOR)-antagonist peptidomimetic ligands as an approach toward effective analgesics with reduced side effects. In this series, a tetrahydroquinoline (THQ) or substituted phenyl is employed to link two key pharmacophore elements, a dimethyltyrosine amino acid and typically an aromatic pendant. Using new and previously reported analogues, we constructed a structure-activity relationship (SAR) matrix that probes the utility of previously reported amine pendants. This matrix reveals that the MOR-agonist/DOR-antagonist properties of these ligands do not change when a tetrahydroisoquinoline (THIQ) pendant is used, despite removal of substituents on the core phenyl ring. Based on this observation, we retained the THIQ pendant and replaced the phenyl core with simpler aliphatic chain structures. These simpler analogues proved to be potent MOR-agonists with high variability in their effects at the DOR and the κ-opioid receptor (KOR). These data show that the amine of the THIQ pendant may be a novel pharmacophore element that favors high MOR-efficacy, whereas the aromatic ring of the THIQ pendant may produce high MOR-potency. Combined, the two pharmacophores within the THIQ pendant may be a structurally efficient means of converting opioid peptides and peptidomimetics into potent and efficacious MOR-agonists.

In vitro pharmacology of fentanyl analogs at the human mu opioid receptor and their spectroscopic analysis.

Opioids are widely misused and account for almost half of overdose deaths in the United States. The cost in terms of lives, health care, and lost productivity is significant and has been declared a national crisis. Fentanyl is a highly potent mu opioid receptor (MOR) agonist and plays a significant role in the current opioid epidemic; fentanyl and its analogs (fentalogs) are increasingly becoming one of the biggest dangers in the opioid crisis. The availability of fentalogs in the illicit market is thought to play a significant role in the recent increase in opioid-related deaths. Although there is both rodent homolog in vivo and in vitro data for some fentalogs, prior to this publication very little was known about the pharmacology of many of these illicit compounds at the human MOR (hMOR). Using gas chromatography-mass spectrometry, nuclear magnetic resonance spectroscopy, and in vitro assays, this study describes the spectral and pharmacological properties of 34 fentalogs. The reported spectra and chemical data will allow for easy identification of novel fentalogs in unknown or mixed samples. Taken together these data are useful for law enforcement and clinical workers as they will aid in the identification of fentalogs in unknown samples and can potentially be used to predict physiological effects after exposure.

Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy µ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

We previously reported a novel SAR campaign that converted a metabolically unstable series of µ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.

Structure-Activity Relationships of 7-Substituted Dimethyltyrosine-Tetrahydroisoquinoline Opioid Peptidomimetics.

The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid receptor, show promise for use in the treatment of addiction, pain, and other conditions. Previously, we reported the creation of bifunctional kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) partial agonist ligands from the classically delta opioid receptor (DOR) antagonist selective dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold through the addition of a 7-benzyl pendant on the tetrahydroisoquinoline ring. This study further explores the structure-activity relationships surrounding 7-position pendants on the Dmt-Tiq scaffold. Some analogues maintain a KOR agonist/MOR partial agonist profile, which is being explored in the development of a treatment for cocaine addiction. Others display a MOR agonist/DOR antagonist profile, which has potential to be used in the creation of a less addictive pain medication. Ultimately, we report the synthesis and in vitro evaluation of novel opioid ligands with a variety of multifunctional profiles.