De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor

Liao, Shiyong; Alfaro-Lopez, Josue; Shenderovich, Mark D.; Hosohata, Keiko; Lin, Jun; Li, Xiaoping; Stropova, Dagmar; Davis, Peg; Jernigan, Kevin; Porreca, Frank; Yamamura, Henry I.; Hruby, Victor J.

doi:10.1021/jm980374r

Cited by 62 publications

(46 citation statements)

References 31 publications

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“…[24][25][26][27][28][29][30] For the ␦ -selective SNC 80 derivatives, controversy exists over whether the pharmacophoric determinants of SNC 80 (and analogs) are the same as those for the ␦ -selective opiates NTI and SIOM. [57][58][59] For the fentanyls and arylacetamides, different yet important discrepancies exist.…”

Section: Selective Nonopiate Ligandsmentioning

confidence: 99%

Molecular recognition of opioid receptor ligands

Kane

Svensson

Ferguson

2006

AAPS J

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A BSTRACTThe cloning of the opioid receptors and subsequent use of recombinant DNA technology have led to many new insights into ligand binding. Instead of focusing on the structural features that lead to increased affi nity and selectivity, researchers are now able to focus on why these features are important. Site-directed mutagenesis and chimeric data have often been at the forefront in answering these questions. Herein, we survey pharmacophores of several opioid ligands in an effort to understand the structural requirements for ligand binding and selectivity. Models are presented and compared to illustrate key sites of recognition for both opiate and nonopiate ligands. The results indicate that different ligand classes may recognize different sites within the receptor, suggesting that multiple epitopes may exist for ligand binding and selectivity.

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Section: Selective Nonopiate Ligandsmentioning

confidence: 99%

Molecular recognition of opioid receptor ligands

Kane

Svensson

Ferguson

2006

AAPS J

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“…The aim of a structureactivity relationship study is to identify the bioactive conformation of a ligand in order to develop potent and selective non-peptide drugs. So far, efforts to obtain potent and selctive non-peptide agonists for G-protein coupled receptors have been more difficult than the efforts to obtain potent and selective antagonists [54]. One reason might be that if the ligand is too small, it can not induce the receptor to change from the inactive to the active conformation because of the lack of contact points between the ligand and the receptor.…”

Section: Structure-affinity and Structure-activity Relationship Studiesmentioning

confidence: 99%

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

2000

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Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to the NPY hormone family and activate a class of receptors called the Y-receptors, and also belong to the large superfamily of the G-protein coupled receptors. Structure-affinity and structure-activity relationship studies of peptide analogs, combined with studies based on site-directed mutagenesis and anti-receptor antibodies, have given insight into the individual characterization of each receptor subtype relative to its interaction with the ligand, as well as to its biological function. A number of selective antagonists at the Y1-receptor are available whose structures resemble that of the C-terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in vivo investigations of the NPY-induced increase in food intake. Y2-receptor selective agonists are the analog cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY and the TASP molecule containing two units of the NPY segment 21-36. Now the first antagonist with nanomolar affinity for the Y2-receptor is also known, BIIE0246. So far, the native peptide PP has been shown to be the most potent ligand at the Y4-receptor. However, by the design of PP/NPY chimera, some analogs have been found that bind not only to the Y4-, but also to the Y5-receptor with subnanomolar affinities, and are as potent as NPY at the Y1-receptor. For the characterization of the Y5-receptor in vitro and in vivo, a new class of highly selective agonists is now available. This consists of analogs of NPY and of PP/NPY chimera which all contain the motif Ala31-Aib32. This motif has been shown to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be the key motif for high Y5-receptor selectivity. The results of feeding experiments in rats treated with the first highly specific Y5-receptor agonists support the hypothesis that this receptor plays a role in the NPY-induced stimulation of food intake. In conclusion, the selective compounds for the different Y receptor subtypes known so far are promising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors.

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“…Efforts have been made in the past to generate molecules, which mimic the orientation of phenyl rings similar to tyrosine and phenylalanine residues of opioid peptides for the developments of peptidomimetics. This resulted in the identification of highly active nonpeptide opioid ligands [20][21][22]. Further, guanidine-and heptamine-derived nonpeptide opioid ligands have been reported by a combinatorial library synthesis approach [23].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation by Opioid Peptidomimetic Compound

Narayan¹,

Singh²,

Agarwal

et al. 2001

Neuroimmunomodulation

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Objective: As a follow-up to our earlier studies on immunomodulation with opioid peptides, we synthesized and evaluated immunomodulatory activity of four peptidomimetic compounds, i.e. Tyr-NH-C(Me)₂-CH₂-O-Phe-NH₂(1), Tyr-NH-C₆H₅-(o)-CH₂-CH₂-O-Phe-NH₂ (2), Tyr-NH-CH₂-CH₂-O-Phe-NH₂ (3) and Tyr-NH-CH(D-Et)-CH₂-O-Phe-NH₂ (4). Methods: These compounds were synthesized in solution phase and evaluated for their immunomodulatory properties in vitro by mixed lymphocyte reaction (MLR), proliferation of opioid receptor-expressing cells, production of tumor necrosis factor-α (TNF-α) and nitric oxide. Results: This study shows the immunosuppressive potential of synthetic peptidomimetic compound 3. This compound inhibited two-way MLR and suppressed the proliferation of the µ-opioid receptor expressing human embryonic kidney cells HEK 293 in vitro. Inhibition of MLR by compound 3 was reversed by naloxone (opioid receptor antagonist) and β-funaltrexamine hydrochloride (µ-opioid receptor antagonist). The immunosuppressive effect of compound 3 was further demonstrated by inhibition of TNF-α and nitric oxide production in lipopolysaccharide-stimulated human PBMCs and mouse macrophage cells RAW 264.7, respectively. Conclusion: These observations suggest that compound 3 inhibits MLR through µ-opioid receptor present on cells.

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De Novo Design, Synthesis, and Biological Activities of High-Affinity and Selective Non-Peptide Agonists of the δ-Opioid Receptor

Cited by 62 publications

References 31 publications

Molecular recognition of opioid receptor ligands

Molecular recognition of opioid receptor ligands

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

Immunomodulation by Opioid Peptidomimetic Compound

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