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
