Morphinan derivatives with an oxabicyclo[3.2.1]octane structure as dual agonists toward δ and κ opioid receptors.

The κ opioid receptor (KOR) is one of the promising targets to develop analgesics lacking morphine like side effects. To seek a novel KOR agonist we designed 6-amide derivatives with an oxabicyclo[3.2.1]octane structure based on a proposed active conformation of a selective KOR agonist nalfurafine. All the synthesized compounds strongly bound to the KOR and some compound showed KOR selectivities. 6R-Amides were more potent and efficacious KOR agonists than the corresponding 6S-isomers. However, most 6-amide derivatives were partial KOR agonist. Conformational analyses of 6R- and 6S-amide derivatives and nalfurafine well accounted for the difference of KOR agonistic activities between two diastereomers. Surprisingly, the tested N-H amides were full δ opioid receptor (DOR) agonists. Among the tested compounds 7a with benzamide moiety was the most potent dual DOR/KOR agonist. On the other hand, 6S-phenylacetamide 8b was potent full DOR agonist with less efficacious agonist activity for the µ receptor and KOR. 6-Amide derivatives with an oxabicyclo[3.2.1]octane structure were expected to be a promising fundamental skeleton for the dual DOR/KOR agonists and/or selective DOR agonists.

C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics.

Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the µ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.

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

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.

Discovery of δ Opioid Receptor Full Inverse Agonists and Their Effects on Restraint Stress-Induced Cognitive Impairment in Mice.

The cyclopropylmethyl group in classical δ opioid receptor (DOR) antagonist NTI, BNTX, and NTB was replaced with various electron-withdrawing groups to develop DOR inverse agonists. N-Benzyl NTB derivative SYK-657 was a potent DOR full inverse agonist and its potency was over 10-fold potent than that of a reference compound ICI-174,864. Intraperitoneal administration of SYK-657 induced the short-term memory improving effect in mice without abnormal behaviors.

Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice.

Our previous results showed that naltrindole (NTI) derivatives with certain types of electron-withdrawing groups as an N-substituent showed δ opioid receptor (DOR) inverse agonistic activities. We therefore synthesized N-acylated NTI derivatives 3a-e and observed that N-benzoyl and N-cyclopropanecarbonyl derivatives SYK-736 (3b) and SYK-623 (3c) were DOR full inverse agonists and the N-acryloyl derivative 3d was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864. Both naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) derivatives with N-benzoyl and N-cyclopropanecarbonyl groups were also DOR full inverse agonists. These N-acylated inverse agonists are interesting compounds because they have no basic nitrogen atom, which has been demonstrated to be an important pharmacophore. NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 (12c) showed dose-dependent antitussive effects in a mouse cough model induced by citric acid exposure. The antitussive effects by SYK-623 and SYK-723 were significantly attenuated by pretreatment with DOR agonist SNC80.