Abstract
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.
Highlights
Opioids have one of the longest known histories of any drug class
We reported that installation of a 7-benzyl pendant on the Tiq could alter the profile of this series to kappa opioid receptor (KOR) agonism/mu opioid receptor (MOR) partial agonism [14]
The profile shown here differs slightly from that previously reported because all compounds reported here display single digit nanomolar or subnanomolar binding at all three opioid receptors
Summary
Opioids have one of the longest known histories of any drug class. The use of opium for ritual, medicinal, and/or recreational purposes dates back to ancient civilizations [1,2]. Discovery morphine, many semi-synthetic and synthetic continues to be revealed, it has posited that unwanted effects and desired effects maysystem result opioids have been developed forbeen this purpose. A result result,from the continues be revealed, it has positedagonist that unwanted effects and desired effectsAs may development of selective agents agonist has declined, and the development ofa multifunctional ligands, the same interaction of an opioid or antagonist with its target. The aim of this work was to explore structure–activity relationships around the 7-benzyl which introduced KOR agonism to the Dmt-Tiq scaffold. Novel analogues reported here reveal pendant which introduced KOR agonism to the Dmt-Tiq scaffold. This work demonstrates development of novel Dmt-Tiq peptidomimetics that display a range of multifunctional opioid profiles. The development of novel Dmt-Tiq peptidomimetics that display a range of multifunctional opioid profiles
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