1426063-41-3Relevant academic research and scientific papers
Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities
Harland, Aubrie A.,Yeomans, Larisa,Griggs, Nicholas W.,Anand, Jessica P.,Pogozheva, Irina D.,Jutkiewicz, Emily M.,Traynor, John R.,Mosberg, Henry I.
, p. 8952 - 8969 (2015/12/09)
In a previously described peptidomimetic series, we reported the development of bifunctional δ-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 δ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-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 (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
Opioid peptidomimetics: Leads for the design of bioavailable mixed efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands
Mosberg, Henry I.,Yeomans, Larisa,Harland, Aubrie A.,Bender, Aaron M.,Sobczyk-Kojiro, Katarzyna,Anand, Jessica P.,Clark, Mary J.,Jutkiewicz, Emily M.,Traynor, John R.
, p. 2139 - 2149 (2013/05/08)
We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (MOR) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.
