Design, Synthesis, and Optimization of Opioid Receptor Peptidomimetics.

Opioids have been used to produce analgesia, euphoria, sleep, and relief from diarrhea and cough. However, opioid use is associated with several negative neurochemical adaptions including tolerance, dependence, and respiratory depression. Studies have shown that selective delta-opioid receptor (DOR) antagonism in the presence of a mu-opioid receptor (MOR) agonist greatly reduces the development of MOR-mediated morphine tolerance and dependence. Unfortunately, multi-drug regimens have complicated pharmacokinetics (PK) and are often impractical to implement in clinical practice due decreased patient compliance stemming from these PK issues. This work describes the design and synthesis of a peptidomimetic series of bi-functional ligands with a mixed-efficacy profile that display MOR agonism and DOR antagonism. These ligands retain the analgesic effect (mediated via MOR agonism) while reducing side effects (mediated via DOR antagonism). In particular, three parallel series of peptidomimetics series were synthesized that retain the key opioid binding elements and orientation of lead peptides, but that eliminate the metabolically labile moieties of the lead peptides, thereby creating more bioavailable ligands. The three parallel series of ligands utilized a tetrahydroquinoline (THQ) core, a tetrahydronaphthalene (THN) core, or an N-acetylated THQ core. N-acetylation increased the affinity of the peptidomimetics for DOR, without significantly altering the subnanomolar affinity and efficacy at MOR, and improved selectivity over the κ-opioid receptor (KOR). Using computational modeling, it was determined that the increase in DOR affinity could be through an interaction between the carbonyl moiety of N-acetylated group and a tyrosine residue in DOR. Additional analogue series were synthesized, including series with 1) various N-substitutions, all of which contain a carbonyl to maintain DOR affinity, 2) several methoxy and hydroxyl moieties to explore SAR, 3) stereochemistry around the THQ and THN core to explore SAR, and 4.) fluorine incorporated to increase bioavailabilty. Of all analogues synthesized and screened for in vivo activity, 54 emerged as having in vivo activity in the Warm Water Tail Withdrawal assay after intraperitoneal administration at 10 mg/kg. Importantly, this compound had a similar duration of action to morphine at the same 10 mg/kg dose and, however unlike morphine, 54 did not produce tolerance upon chronic administration.PhDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120692/1/aharland_1.pd

Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy

In an effort to expand the structure–activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the <i>o-</i> or <i>m-</i>positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the <i>p</i>-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of <b>8c</b>, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ‑Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through <i>N</i>-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (<b>14a</b>) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h

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

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