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

Abstract

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.

Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors

“…Alternatively, a biphenyl group was introduced to afford FW-AII-OH-1 and FW-AII-OH-2 ( Figure 3 b), which were identified as selective agonists of KOR and DOR, respectively. Since a hydrophobic pocket formed by Trp 6.48 and Tyr 7.43 (Ballesteros–Weinstein numbering [ 23 ]) existed around the “message” part [ 24 ], and the phenylethyl was introduced to the protonated nitrogen atom to obtain FW-DⅢ-OH-2 , which increased the size of the “message” part. Whether such structural changes shared a similar pharmacological function with that of FW-AII-OH-1 and FW-AII-OH-2 , FW-DⅢ-OH-2 was found to have moderate affinity with DOR.…”

Design, Synthesis, and Structure–Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective μ Opioid Receptor Agonists

“…Binding affinities were determined by competitive binding with [ 3 H] DAMGO (μ opioid receptor, MOR), [ 3 H] DPDPE (δ opioid receptor, DOR), [ 3 H] U50488 (κ opioid receptor, KOR) in CHO cell expressing MOR, DOR, KOR, respectively, as described in the literature , and summarized in Table . Efficacies were determined in membrane preparations expressing MOR, DOR, and KOR in the CHO cell using [ 35 S] GTPγS assay , and summarized in Table .…”

“…In spite of this, tramadol displays some mild to moderate adverse effects: nausea, dizziness, constipation, vomiting, somnolence, and headache . Recently, starting from tramadol as a lead compound, our group discovered selective MOR agonists and highly selective, potent DOR agonists based on the classic “message-address” concept. , Herein, as part of our ongoing interest of tramadol, we further disclosed our efforts on the discovery and structure–activity relationship of (3 R , 4 S )-3-((dimethylamino)­methyl)-4-(3-hydroxyphenyl)-1-(3-(trifluoromethyl)­phenethyl)­piperidin-4-ol hydrochloride as a novel, selective, and potent MOR agonist.…”

In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP

“…Therefore, we suggest that the mechanical and thermal analgesic effects seen in the first 2 h of measurements after tramadol administration are mainly induced by O-Dt, which acts as a mu receptor agonist, eliciting naloxone-sensitive analgesic effects [ 56 ]. Interestingly, a recent structure–activity study of tramadol and its metabolite proved that O-Dt and morphine share common pharmacophore features with, and have similar binding modes to, the mu opioid receptor [ 57 ]. The experimental data suggest that tramadol and its metabolite, O-DT, exert their analgesic effect through the direct activation of mu opioid receptors, but also through the indirect activation of central α2-adrenoceptors [ 58 , 59 ] and descending serotonergic pathways [ 60 ].…”