Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration

Yoshikazu Watanabe; Kohei Hayashida; Daisuke Saito; Toshihiro Takahashi; Junichi Sakai; Eriko Nakata; Takashi Kanda; Takashi Iwai; Shigeto Hirayama; Hideaki Fujii; Tomio Yamakawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2017.05.072

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3495-3498. doi: 10.1016/j.bmcl.2017.05.072. Epub 2017 May 26.

Authors

Affiliations

¹ Discovery Research Laboratories, Nippon Chemiphar Co., Ltd, 1-22, Hikokawado, Misato, Saitama 341-0005, Japan.
² Discovery Research Laboratories, Nippon Chemiphar Co., Ltd, 1-22, Hikokawado, Misato, Saitama 341-0005, Japan; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
³ Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁴ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁵ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; International Institute for Integrative Sleep Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan. Electronic address: nagase.hiroshi.gt@u.tsukuba.ac.jp.

PMID: 28602640
DOI: 10.1016/j.bmcl.2017.05.072

Abstract

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.

Keywords: Analgesic effect; Azatricyclodecane skeleton; Blood-brain-barrier permeability; DOR agonist; Opioid.

Publication types

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

MeSH terms

Administration, Cutaneous
Analgesics, Opioid / chemical synthesis
Analgesics, Opioid / chemistry
Analgesics, Opioid / pharmacokinetics*
Analgesics, Opioid / pharmacology*
Animals
Blood-Brain Barrier / metabolism*
Cyclodecanes / chemical synthesis
Cyclodecanes / chemistry
Cyclodecanes / pharmacokinetics*
Cyclodecanes / pharmacology*
Drug Design
Humans
Mice
Receptors, Opioid, delta / agonists*
Receptors, Opioid, delta / metabolism

Substances

Analgesics, Opioid
Cyclodecanes
Receptors, Opioid, delta