Design and synthesis of quinolinopropellane derivatives with selective δ opioid receptor agonism

Hiroshi Nagase; Ryo Nakajima; Naoshi Yamamoto; Shigeto Hirayama; Takashi Iwai; Toru Nemoto; Hiroaki Gouda; Shuichi Hirono; Hideaki Fujii

doi:10.1016/j.bmcl.2014.04.098

Design and synthesis of quinolinopropellane derivatives with selective δ opioid receptor agonism

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2851-4. doi: 10.1016/j.bmcl.2014.04.098. Epub 2014 May 4.

Authors

Hiroshi Nagase¹, Ryo Nakajima², Naoshi Yamamoto³, Shigeto Hirayama⁴, Takashi Iwai⁴, Toru Nemoto⁴, Hiroaki Gouda⁵, Shuichi Hirono⁶, Hideaki Fujii⁴

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: nagase.hiroshi.gt@u.tsukuba.ac.jp.
² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
⁴ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁵ Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
⁶ Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

PMID: 24835200
DOI: 10.1016/j.bmcl.2014.04.098

Abstract

Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a-d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand-DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation.

Keywords: Binding free energy; Binding mode; DOR; Opioid; Propellane structure.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bridged-Ring Compounds / chemical synthesis
Bridged-Ring Compounds / chemistry
Bridged-Ring Compounds / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Conformation
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Receptors, Opioid, delta / agonists*
Structure-Activity Relationship

Substances

Bridged-Ring Compounds
Quinolines
Receptors, Opioid, delta