Synthesis and Evaluation of Mixed Efficacy Mu Opioid Receptor (MOR), Delta Opioid Receptor (DOR) Peptidomimetic Ligands.

[摘要] Reported here is a structure activity relationship (SAR) study on a series of mixed efficacy mu opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist ligands featuring a tetrahydroquinoline (THQ) scaffold. A diverse set of substitutions at the 6-position of the THQ core has revealed a number of important trends. Attachment of this pendant at a basic nitrogen resulted in a number of analogues that showed superior binding affinity and potency at MOR, with improved binding affinity at the kappa opioid receptor (KOR). In particular, N-acetylated, tetrahydroisoquinoline analogue 102 showed equal, subnanomolar binding affinity for MOR, DOR and KOR, with a low nanomolar EC50 at MOR and no stimulation at DOR. 102, in addition to isoindoline analogue 86, were also shown to produce dose dependent antinociception in the mouse warm water tail withdrawal (WWTW) assay, with both compounds having a total duration of action comparable to morphine, an improvement on lead peptidomimetic 1. Substitution of the THQ aniline with a variety of heteroatoms was found to maintain subnanomolar MOR binding affinity and high efficacy, although only thiochroman analogue 214 was found to produce a dose dependent antinociceptive effect in the WWTW assay, with a duration of action comparable to 86 and 102. Expansion or contraction of the THQ ring system was detrimental to the overall desired MOR agonist/DOR antagonist profile, with MOR potency being particularly affected. A 3-step synthesis of Boc-2’,6’-dimethyl-L-tyrosine featuring a microwave-assisted Negishi coupling is also described, which led to the expedient synthesis of novel tyrosine analogues that were incorporated into the peptidomimetic scaffold. Of particular interest is 2’,6’-dichloro-L-tyrosine intermediate 243, which may be useful for the development of peptidomimetics with reduced liability for oxidative metabolism on the aryl methyl groups, and carboxamido peptidomimetic 251, which shows a total duration of action in vivo that is comparable to lead compound 1. An alternative series of peptidomimetics featuring a piperidine or piperazine core is also discussed. In this series, it was found that an increase in the length of the hydrophobic chain at position 4 corresponds to an improved efficacy at MOR.

[发布机构] University of Michigan

[效力级别] Peptidomimetic

[关键词] Opioid;Peptidomimetic;Chemistry;Science;Medicinal Chemistry