7ß-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7ß-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7ß-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7ß-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7ß-methyl orvinol analogues. Surprisingly, SLL-603, a 7ß-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7ß-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.

Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel µ opioid receptor ligands.

AIM: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton. METHODS: Based on a three-dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the µ opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N-phenethylnormorphine was docked to the µ opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics. RESULTS: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the µ opioid receptor were comparatively studied. CONCLUSION: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design.

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities.

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (Ki = 0.4 ± 0.1 nM) and the highest selectivity (µ/κ = 339, δ/κ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED50 = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED50 = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.