|Title||Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Deekonda S, Wugalter L, Rankin D, Largent-Milnes TM, Davis P, Wang Y, BassiriRad NM, Lai J, Kulkarni V, Vanderah TW, Porreca F, Hruby VJ|
|Journal||Bioorg Med Chem Lett|
|Date Published||2015 Oct 15|
|Keywords||Analgesics, Animals, Dose-Response Relationship, Drug, Drug Design, Enkephalins, Guinea Pigs, Ligands, Mice, Molecular Conformation, Muscle Contraction, Pain Measurement, Pain Threshold, Piperidines, Rats, Rats, Sprague-Dawley, Receptors, Opioid, Structure-Activity Relationship|
We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
|Alternate Journal||Bioorg. Med. Chem. Lett.|
|PubMed Central ID||PMC4642889|
|Grant List||P01 DA006284 / DA / NIDA NIH HHS / United States |
R01 DA013449 / DA / NIDA NIH HHS / United States
2P01 DA006284 / DA / NIDA NIH HHS / United States
314450 / / PHS HHS / United States
Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.
Faculty Member Reference:
Victor Hruby, Ph.D.
Tally Largent-Milnes, PhD
Frank Porreca, Ph.D.
Todd Vanderah, Ph.D.