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Bioorg Med Chem Lett. 2015 Aug 1;25(15):2927-30. doi: 10.1016/j.bmcl.2015.05.038. Epub 2015 May 22.

Naltrindole derivatives with fluorinated ethyl substituents on the 17-nitrogen as δ opioid receptor inverse agonists.

Author information

1
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
2
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiih@pharm.kitasato-u.ac.jp.

Abstract

We synthesized derivatives of the δ opioid receptor (DOR) antagonists naltrindole (NTI) and compound 1 that were modified with small alkyl or fluorinated ethyl substituents on the 17-nitrogen. Although the derivatives showed decreased binding affinities for the opioid receptors, their selectivities for the DOR were higher than the parent compounds NTI and compound 1. Surprisingly, 17-fluoroethyl NTI derivatives exerted DOR inverse agonistic activities. The DOR inverse agonism of compounds 4c-e was less efficacious but significant, as compared with a standard DOR inverse agonist ICI-174864. On the other hand, compound 1 and its derivatives with small alkyl or monofluoroethyl substituents were partial agonists, but the derivatives having di- or trifluoroethyl group showed neither agonistic nor inverse agonistic activities.

KEYWORDS:

Fluoroalkyl substituent; Inverse agonist; NTI derivative; δ opioid receptor

PMID:
26048798
DOI:
10.1016/j.bmcl.2015.05.038
[Indexed for MEDLINE]

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