Novel selective κ agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion

Wei, Yuanyuan; Ma, Yan; Yao, Song-Yu; Kong, Linghui; Xiao, Lan; Chai, Jing-Rui; Chen, Jing; Li, Wei; Wang, Yujun; Shao, Liming; Liu, Jing-Gen

doi:10.1038/s41401-021-00761-x

Cited by 5 publications

(8 citation statements)

References 46 publications

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“…As the positive control, U50,488H at an antinociceptive ED 50 dose of 5 mg/kg produced significant CPA. In contrast, SLL-039 and SLL-1206 , another two morphinan-based selective KOR agonists, also exhibited significant less aversion at effective analgesic doses compared to U50,488H , as shown in our previous work. , …”

Section: Resultsmentioning

confidence: 64%

“…In contrast, SLL-039 and SLL-1206, another two morphinan-based selective KOR agonists, also exhibited significant less aversion at effective analgesic doses compared to U50,488H, as shown in our previous work. 16,34 Locomotor Activities. Next, the effect of SLL-627 treatment on locomotor activity was also evaluated in mice.…”

Section: Chemistrymentioning

confidence: 99%

“…This pharmacological characteristic has been reproduced in other morphinan-based KOR agonists described in our previous work. 16,34 However, there are wide variations in sedation among morphinan-based KOR agonists. Nalfurafine exhibited strong sedation, which was claimed to be the reason for abandoning the indication of pain.…”

Section: Chemistrymentioning

confidence: 99%

“…The experiment was carried out to assess sedative side effects with ICR mice according to our previous study. 34 The rotarod system was equipped with automatic recording system (the test time and acceleration time was 240 s; the minimum rotation speed was 4 r/min; the maximum rotation speed was 40 r/min). The mice were trained three times per day for 2 days, and mice with baseline of >160 s were screened for following test.…”

Section: N-cyclopropylmethyl-7α-methyl-7β-(p-methylphenylcarbonyl)-6α...mentioning

confidence: 99%

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SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

et al. 2022

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Undue central nervous system (CNS) side effects including dysphoria and sedation remain to be a challenge for the development of κ opioid receptor (KOR) agonists as effective and safe analgesics. On the basis of our previous work on morphinan-based KOR agonists, a series of 7α-methyl-7β-substituted northebaine derivatives were designed, synthesized, and biologically assayed. Among others, compound 4a (SLL-627) has been identified as a highly selective and potent KOR agonist both in vitro and in vivo, and its molecular basis was also examined and discussed. Besides low liability to conditioned place aversion (CPA) test, treatment of SLL-627 was associated with a nonreduction in locomotor activity, compared to most of the other arylacetamide- or morphinan-based KOR agonists which generally exhibited apparently sedative effects. This unexpected finding provides new insights to dissociate analgesia from sedation for future discovery of innovative KOR agonists.

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Section: Resultsmentioning

confidence: 64%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: N-cyclopropylmethyl-7α-methyl-7β-(p-methylphenylcarbonyl)-6α...mentioning

confidence: 99%

See 2 more Smart Citations

SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

et al. 2022

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“…Sedative side effects were assessed in male ICR mice utilizing a rotarod apparatus, equipped with an automated recording feature, following a protocol previously delineated. 37 The rotarod system was equipped with an automatic recording system (the test time and acceleration time were 240 s; the minimum rotation speed was 4 rpm; and the maximum rotation speed was 40 rpm). The mice were trained three times per day for two consecutive days, and mice with baseline >160 s were screened for the following test.…”

Section: N-cyclopropylmethyl-7α-[2′-(n′-methyl-n′-p-trifluoromethylbe...mentioning

confidence: 99%

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Li,

Ye,

et al. 2024

J. Med. Chem.

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Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, K i = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [ 35 S]GTPγS binding, EC 50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED 50 = 0.20−0.30 mg/kg, i.p.; abdominal constriction test, ED 50 = 0.20−0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED 50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

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Endogenous opiates and behavior: 2022

Bodnar

2023

Peptides

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Novel selective κ agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion

Cited by 5 publications

References 46 publications

SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Endogenous opiates and behavior: 2022

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