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

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

  • Bioorg Med Chem Lett. 2015 Aug 1;25(15):2927-30. doi: 10.1016/j.bmcl.2015.05.038.
Toru Nemoto 1,  Yusuke Iihara 1,  Shigeto Hirayama 1,  Takashi Iwai 1,  Eika Higashi 1,  Hideaki Fujii 2,  Hiroshi Nagase 1
Affiliations

Affiliations

  • 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.
PMID: 26048798 DOI: 10.1016/j.bmcl.2015.05.038
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.

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