Synthesis of novel analogues of the delta opioid ligand SNC-80 using AlCl3-promoted aminolysis

Barn, David R.; Bom, A.; Cottney, Jean; Caulfield, Wilson; Morphy, J. Richard

doi:10.1016/s0960-894x(99)00174-2

Cited by 26 publications

(23 citation statements)

References 6 publications

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“…Moreover, it has been shown that substitution of the benzyl group with even larger residues like the N -3,4-(methylenedioxy)benzyl moiety (Fig. 6B) can be beneficial for DOP affinity ( 30 ). The docking pose of this analog reveals that it can penetrate further into the entrance of the sodium-binding pocket with only minor adjustment in the pocket-lining side chains, stabilized by a hydrogen bond to S311 7.46 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

et al. 2019

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Selective activation of the -opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to -opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects. RESULTS Activation-related changes in the DOPBoth agonist-bound structures are in an activated state. Unless otherwise indicated, we will use the higher-resolution BRIL-DOP-KGCHM07 structure for comparison with previously published inactive-state antagonist-bound DOP structures [Protein Data Bank (PDB) 4N6H and 4RWD] (16, 17) and with active-state structures of the MOP (PDB 5C1M and 6DDF) (18,20) and KOP (PDB 6B73) (19). First, the agonist-bound DOP structures display large outward movements of the intracellular parts of helices V (4.5 Å) and VI (9.4 to 11.2 Å), and a 3.9 Å inward movement of helix VII ( Fig. 2A), which is a common feature of the active conformational states of GPCRs (21). The shift of helix VII at the level of residue N314 7.49 [superscripts according to the Ballesteros and Weinstein numbering (22)] (Fig. 3A), which leads to a collapse of the allosteric sodium-binding pocket in active-state GPCR structures (23), is even more pronounced in the determined DOP structures as compared to the active MOP and KOP (Fig. 3B and fig. S1). However, this greater shift of N314 7.49 in the DOP might be affected by three mutations in the sodium-binding pocket (N90 2.45 S, D95 2.50 G, N131 3.35 S) that were introduced during construct design. The activation-related outward movement of helix VI at the level of residue F270 6.44 is greater in the agonist-bound DOP than in the MOP and KOP. On the contrary, the very tips of helix VI (at position 6.28 as a reference) are more tilted by 4 to 6 Å in the active-state MOP and KOP ( fig. S1), likely due to the bound G protein or nanobody, respectively, pushing helix VI tips further outward (24). Elucidating the active -opioid receptor crystal structure with peptide and smallmolecule agonists. Sci. Adv. 5, eaax9115 (2019).

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Section: Resultsmentioning

confidence: 99%

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

et al. 2019

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“…Furthermore, it can be anticipated that a pure delta agonist, devoid of mu receptor‐mediated activity, would be biologically active and display a pharmacological profile highly distinct from that of the well‐known opiates in clinical use. At present, BW373U86 (Chang et al ., 1993) and derived compounds have proved weakly potent in models of acute pain (Wild et al ., 1993; Bilsky et al ., 1995; Barn et al ., 1999), and in addition, show convulsive properties (Broom et al ., 2002). Other compounds are under development (Wei et al ., 2000; Dondio et al ., 2001) and potential therapeutic areas could be chronic pain conditions and mood disorders (Filliol et al ., 2000).…”

Section: Discussionmentioning

confidence: 99%

The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

Scherrer¹,

Befort²,

Contet

et al. 2004

Eur J of Neuroscience

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Delta-selective agonists have been developed to produce potent analgesic compounds with limited side-effects. DPDPE and deltorphin II are considered prototypes, but their delta-selectivity in vivo and the true ability of delta receptors to produce analgesia remain to be demonstrated. Here we have performed a parallel analysis of mu, delta and combinatorial opioid receptor knockout mice, in which we found no obvious alteration of G-protein coupling for remaining opioid receptors. We compared behavioural responses in two models of acute thermal pain following DPDPE and deltorphin II administration by intracerebroventricular route. In the tail-immersion test, both compounds were fully analgesic in delta knockout mice and totally inactive in mu knockout mice. In the hotplate test, the two compounds again produced full analgesia in delta knockout mice. In mu knockout mice, there was significant, although much lower, analgesia. Furthermore, DPDPE analgesia in the delta knockout mice was fully reversed by the mu selective antagonist CTOP in both tests. Together, this suggests that mu rather than delta receptors are recruited by the two agonists for the tail withdrawal and the hotplate responses. Finally, deltorphin II slightly prolonged jump latencies in double mu/kappa knockout mice (delta receptors only) and this response was abolished in the triple knockout mice, demonstrating that the activation of delta receptors alone can produce weak but significant mu-independent thermal antinociception.

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“…Researchers at Organon have outlined the solid phase synthesis of targeted libraries of δ−opioid receptor ligands based upon the 1-benzhydryl-4-benzyl-piperazine core [53].…”

Section: Opioid Receptorsmentioning

confidence: 99%

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

Shuttleworth¹,

Connors²,

Fu³

et al. 2005

CMC

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This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

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Synthesis of novel analogues of the delta opioid ligand SNC-80 using AlCl3-promoted aminolysis

Cited by 26 publications

References 6 publications

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

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