Opioid κ Receptors as a Molecular Target for the Creation of a New Generation of Analgesic Drugs

Grechko, O. Yu.; Spasov, A. A.; Dm, Shtareva

doi:10.1007/s11094-016-1388-z

Cited by 5 publications

(20 citation statements)

References 103 publications

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“…1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 4.60 (s, 1H), 3.87 (s, 3H), 3.21 (t, J = 12.7 Hz, 1H), 3.18 (s, 3H), 3.10 (d, J = 6.1 Hz, 1H), 3.00 (dd, J = 20.8, 12.8 Hz, 2H), 2.71 (dd, J = 11.6, 4.9 Hz, 1H), 2.34 (tdd, J = 19.7, 13.6, 6.3 Hz, 4H), 2.18 (td, J = 12.7, 5.5 Hz, 1H), 1.74 (dd, J = 12.9, 2.4 Hz, 1H), 1.68−1.59 (m, 2H), 1.42 (td, J = 12.2, 6.1 Hz, 1H), 1.31 (td, J = 12.7, 6.1 Hz, 1H), 0.90−0.83 (m, 1H), 0.82−0.75 (m, 1H), 0.51−0.42 (m, 2H), 0.10 (d, J = 4.1 Hz, 2H). 13 N-Cyclopropylmethyl-7α-4′-methylaminophenyl-6,14endoethanotetrahydronorthebaine, Compound 9a. N,N-Diisopropyl-ethylamine (34 mg, 0.26 mmol was added to a solution of 8 (100 mg, 0.21 mmol) in DCM (1 mL), after which benzyl chloroformate (39 mg, 0.23 mmol) was added dropwise at 0 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…1 H NMR (600 MHz, CDCl 3 ) δ 7.14 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.4 Hz, 3H), 5.30 (s, 1H), 4.60 (s, 1H), 3.87 (s, 3H), 3.20 (s, 1H), 3.17 (s, 3H), 3.14 (q, J = 7.1 Hz, 2H), 3.07 (s, 1H), 3.00 (dd, J = 21.9, 14.6 Hz, 2H), 2.67 (s, 1H), 2.32 (d, J = 21.6 Hz, 4H), 2.17 (s, 1H), 1.74 (d, J = 12.0 Hz, 1H), 1.67 (d, J = 13.0 Hz, 1H), 1.62 (dd, J = 13.5, 7.0 Hz, 1H), 1.42 (dd, J = 16.1, 10.3 Hz, 1H), 1.35−1.29 (m, 1H), 1.26−1.19 (m, 3H), 0.88−0.82 (m, 1H), 0.77 (s, 1H), 0.51−0.41 (m, 2H), 0.10 (s, 2H). 13 N-Cyclopropylmethyl-7α-4′-propylaminophenyl-6,14endoethanotetrahydronorthebaine, Compound 9c. A solution of palladium on carbon (5%, 46 mg) in isopropyl alcohol was added to a solution of ammonium formate (200 mg, 3.2 mmol) in H 2 O (1 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…1 H NMR (600 MHz, CDCl 3 ) δ 7.13 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 7.4 Hz, 1H), 6.59 (dd, J = 19.8, 7.9 Hz, 4H), 5.41 (s, 1H), 4.63 (s, 1H), 3.88 (s, 4H), 3.22 (d, J = 11.2 Hz, 1H), 3.18 (s, 3H), 3.12−3.00 (m, 5H), 2.37 (s, 5H), 2.00−1.79 (m, 3H), 1.63 (dt, J = 14.8, 7.5 Hz, 4H), 0.99 (t, J = 7.4 Hz, 3H), 0.96 (d, J = 6.7 Hz, 1H), 0.94−0.90 (m, 1H), 0.52 (s, 2H), 0.16 (s, 2H). 13 N -C y cl o p r o p y l m e t h yl -7α -4 ′ -cy c l o p h e n y l m e t h ylaminophenyl-6,14-endoethanotetrahydronorthebaine, Compound 9d. Sodium carbonate (67 mg, 0.63 mmol) and (bromomethyl)cyclopropane (43 mg, 0.32 mmol) were added to a solution of 8 (100 mg, 0.21 mmol) in DMF (2 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

et al. 2019

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Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, K i = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

et al. 2019

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“…Its activation appears to play a potential role in the treatment of pain, substance use disorders, , and mania . Notably, most of the κOR agonists are potent analgesics , without producing respiratory depression, physical dependence, or other typical opioid-like effects associated with stimulation of the μ opioid receptor (μOR). , Because of this feature, κOR has been identified as a promising target for nonaddictive analgesics.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Liu

Jiang

Kong

et al. 2021

ACS Chem. Neurosci.

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κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent κOR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure−activity relationships (SARs) of arylacetamides in conferring κOR agonistic activities could be reproduced by these analogues. Thus, a series of Ncyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3′,4′-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the κOR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective κOR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro. The resultant SARs were inconsistent with that of classical arylacetamides as κOR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring κOR activities.

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“…These include the design of κ or δ opioid selective agonists, new bifunctional µ receptor agonists (µ/δ, µOR-NRI, NOP/µOR) and G protein-biased ligand. The κ opioid agonists can offer effective analgesia without causing typical opioid-related adverse effects, which means selective κ opioid can serve agonists as analgesics (Assana et al, 2014;Grechko et al, 2016;Zaitseva et al, 2018). Similarly, the δ opioid receptor (δOR) has also been identified as a potent target for the discovery of novel analgesic drugs, with less side effects and better analgesia in animal models (Desmeules et al, 1993;Fraser et al, 2000;Brandt et al, 2001;Mika et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Use of Computational Approaches in the Discovery and Mechanism Study of Opioid Analgesics

Zhao

Sun

et al. 2020

Front. Chem.

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Opioid receptors that belong to class A G protein-coupled receptors (GPCRs) are vital in pain control. In the past few years, published high-resolution crystal structures of opioid receptor laid a solid basis for both experimental and computational studies. Computeraided drug design (CADD) has been established as a powerful tool for discovering novel lead compounds and for understanding activation mechanism of target receptors. Herein, we reviewed the computational-guided studies on opioid receptors for the discovery of new analgesics, the structural basis of receptor subtype selectivity, agonist interaction mechanism, and biased signaling mechanism.

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Opioid κ Receptors as a Molecular Target for the Creation of a New Generation of Analgesic Drugs

Cited by 5 publications

References 103 publications

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

The Use of Computational Approaches in the Discovery and Mechanism Study of Opioid Analgesics

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