b昢 lackwell Acta Pharmacologica Sinica 2005 Mar: 26(3): 334-3 Publishing Full-length article Structural comparisons of meptazinol with opioid analgesics Wei LI, Jing-lai HAO, Yun TANG, Yan CHEN, Zhui-bai QIU2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200032, China Key words Abstract meptazinol; tramadol; opioid analgesics, Aim: To investigate the mechanism of action of a potent analgesic, (*)-meptazinol Methods: The structures of meptazinol enantiomers were compared with opioid pharmacophore and tramadol. Results: Neither enantiomer of meptazinol fitted Science Foundation of China(Ng 30271539, any patterns among the opioid pharmacophore and tramadol, although they did 2003-2005) share some structural and pharmacological similarities. However, the structure ce to Prof Zhui bai QIU. superpositions implied that both enantiomers of meptazinol might share some Phn86-21-5423-7595 similar analgesic mechanisms with ty pical opiate analgesics. Conclusion Fax86-21-5423-7264 E-mail zbqiuashmu.edu.cn Meptazinol should have a different mechanism of action to known analgesics, which would be helpful in further investigations of meptazinol in the search for Received 2004-05-20 non-addictive analgesics cal structure of meptazinol is similar to that of (+)-Meptazinol(Figurel), with one chiral center in the(Figure 1),(ii) meptazinol-induced analgesia is almost com- structure, is a potent analgesic similar to pethidine. Included pletely reversed by the opioid antagonist naloxone, although in the British Pharmacopoeia in 1998,(*)-meptazinol was higher doses are required to reverse meptazinol compared to recommended by Hoskin and Hanks as one of six widely morphine; (iii)meptazinol is believed to be a selective u used agonist-antagonist analgesics 21. However, to date its opioid agonist 4)l, and (iv)meptazinol reverses the sig analgesic mechanism remains unknown. For example, we are acute morphine overdose in animals and precipitates still unsure if it is an agonist, an antagonist, or even a mixed nence in animals rendered physically dependent on agonist-antagonist, and whether it acts on one target or morphine multiple targets However, unlike typical opiates whose notorious side During the early stages of development, meptazinol was effects include respiratory depression and addiction, regarded as a mixed agonist-antagonist opioid analgesic meptazinol induces little respiratory depression and has low based on the following experimental evidences: (i)the chemi- addictive potential5,6I. These properties make meptazinol 1119N- CH3 H3C-N CH3 6 HO3 H2CO321423 Meptazinol (1) Tramadol (3) Figure 1. The structure of meptazinol, morphine, and tramadol c2005 CPs and sIMMWei LI, Jing-lai HAO, Yun TANG, Yan CHEN, Zhui-bai QIU2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200032, China (±)-Meptazinol (Figure1), with one chiral center in the structure, is a potent analgesic similar to pethidine. Included in the British Pharmacopoeia in 1998[1], (±)-meptazinol was recommended by Hoskin and Hanks as one of six widely used agonist–antagonist analgesics[2]. However, to date its analgesic mechanism remains unknown. For example, we are still unsure if it is an agonist, an antagonist, or even a mixed agonist–antagonist, and whether it acts on one target or multiple targets. During the early stages of development, meptazinol was regarded as a mixed agonist–antagonist opioid analgesic based on the following experimental evidence[3]: (i) the chemi￾cal structure of meptazinol is similar to that of morphine (Figure 1); (ii) meptazinol-induced analgesia is almost com￾pletely reversed by the opioid antagonist naloxone, although higher doses are required to reverse meptazinol compared to morphine; (iii) meptazinol is believed to be a selective µ opioid agonist[4]; and (iv) meptazinol reverses the signs of acute morphine overdose in animals and precipitates absti￾nence in animals rendered physically dependent on morphine. However, unlike typical opiates whose notorious side￾effects include respiratory depression and addiction, meptazinol induces little respiratory depression and has low addictive potential[5,6]. These properties make meptazinol Figure 1. The structure of meptazinol, morphine, and tramadol. Aim: To investigate the mechanism of action of a potent analgesic, (±)-meptazinol. Methods: The structures of meptazinol enantiomers were compared with opioid pharmacophore and tramadol. Results: Neither enantiomer of meptazinol fitted any patterns among the opioid pharmacophore and tramadol, although they did share some structural and pharmacological similarities. However, the structure superpositions implied that both enantiomers of meptazinol might share some similar analgesic mechanisms with typical opiate analgesics. Conclusion: Meptazinol should have a different mechanism of action to known analgesics, which would be helpful in further investigations of meptazinol in the search for non-addictive analgesics. meptazinol; tramadol; opioid analgesics; pharmacophore 1 Project supported by the National Natural Science Foundation of China (No 30271539, 2003-2005). 2 Correspondence to Prof Zhui-bai QIU. Phn 86-21-5423-7595 Fax 86-21-5423-7264. E-mail zbqiu@shmu.edu.cn Received 2004-05-20 Accepted 2004-11-20 doi: 10.1111/j.1745-7254.2005.00045.x