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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.

Abstract：

: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, Ki = 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Xiao L,Wang Y,Zhang M,Wu W,Kong L,Ma Y,Xu X,Liu X,He Q,Qian Y,Sun H,Wu H,Lin C,Huang H,Ye R,Jiang S,Ye RF,Yuan C,Fang S,Xue D,Yang X,Chen H,Zheng Y,Yu L,Xie Q,Zheng L,Fu W,Li W,Qiu Z,Liu J,Shao

doi

10.1021/acs.jmedchem.9b00857

subject

Has Abstract

pub_date

2019-12-26 00:00:00

pages

11054-11070

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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