Provided for non-commercial research and education use Not for reproduction, distribution or commercial use Bioorganic Medicinal Chemistry Letters The Tetrahedron Journal for Research at the Interface of chemistry and Biology Ed aoe.in- Chiet DALE L BOGER . Science Direct This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article(e.g in Word or Tex form)to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
Author's personal copy Bioorganic Medicinal Chemistry Letters 20 (2010)418-421 Contents lists available at Science Direc Bioorganic Medicinal Chemistry Letters LSEVIER journalhomepagewww.elsevier.com/locate/bmcl Highly selective and potent H opioid ligands by unexpected substituent on morphine skeleton Wei Lia, Yi-Min Tao b. Yun Tang, Xue-Jun Xu, Jie Chen Wei Fu a, Xing-Hai Wang Bo Chao Vei sheng, Qiong Xie Zhui-Bai Qiu, Jing-Gen Liu n Road, Shanghai 200032, China ate Key Laboratory of Drug Research, Shanghai Institute of materia Medica, Chinese Academy of sciences, Shanghai 201203, China eSchool of pharmacy. East China University of Science 8 Technology, 130 Meilong Road, Shanghai 200237, China ARTICLE INFO ABSTRACT Unexpected substituent on the well-known morphine skeleton is described to be account for highly Received 10 selective and potent H opioid ligands, which is strongly connected to substituted aromatic groups on this omitted 8a-position. ccepted 27 July 2009 Available online 29 july 2009 e 2009 Elsevier Ltd. All rights reserved. Selective ligands Thebaine(Fig. 1)is a naturally occurred alkaloid isolated from experimentally and theoretically. However, the So-adducts have opium. Though it bears much similar structure with morphine, been not considered seriously because not only are they not acces- thebaine is inactive as analgesic with very low affinities to opioid sible through the cycloaddition of thebaine and receptors.However, it could be converted to a variety of potent date, but also significant decrease in analgesic served in the through several organic transformations And the Diels-Alder rea known analogue in comparison to their main 7a-counterparts tion of thebaine with dienophiles is obviously the most valuable n this Letter we reported unexpected Sa-adducts yielded from one among these reactions, which leads to the discovery of extre- thebaine and styrenes which bear obviously different SARs(Struc mely highly active analgesics than morphine. And due to less ture-Activity Relationships) with other oripavine. And the substi- selective characters of these so-called oripavine yielded from tuent on the C8-position is strongly linked with u opioid agonistic 已 pretor activity and selectivity which has been omitted before. phine and Etorphine has been used universally for opioid A straightforward synthetic strategy was developed( Scheme 1), receptors. and thebaine was preferably attacked by styrenes from the less It is widely accepted that subtle differences in critical structural bulky B face to afford 6a, 14a-endo-ethenotetrahydrothebaine. loci of bioactive compounds may result in great changes in biolog- In addition to known 7o-adducts yielded as main products, uney ical responses. And these may provide useful information on drug- pected by-products were separated in case of styrene, m-nitrosty- receptor interactions and on receptor characteristics. Since the rene and p-nitrostyrene Follow-up works examined compound-5 greatly enhanced biological activities were suggested strongly to by X-ray crystallography( Fig. 2, compound-5, CCDC 696689)and be linked with the substituent on C7 positior found it was a regioisomeric So-adduct in comparison to its main accommodated at the postulated lipophilic domain on the opioid 7a-adduct(compound-4, CCDC 696688) Similar large deshielding receptor, it was desirable to investigate other cycloadducts of the- effect to the proximity of the tertiary amine is observed for H-8B in baine with dienophiles besides the well investigated 7a-adducts H NMR spectra of all regioisomeric adducts, as well as character istic resonances of H7B upfield due to absence of substitution (Table 1) And normal 7B-adducts as were absent (Table 1). Corresponding authors. TeL: +86 21 54237595: fax: +86 21 54237264(Z-B.Q) In the absence of the polarizing methoxy functionality at C-6 of tel+862150807588UGL E-mailaddresses:zbqiu@shmu.edu.cn(Z-B.Qiu).jgliuemailshcncaccn(. thebaine Diels-Alder addition to 3-buten-2-one can give a regio- isomeric adduct in which the acetyl group is attached at C-8. Both authors contribute equally to this work. And the Diels-Alder addition to styrenes may afford similar 0960-894x/S- see front matter e 2009 Elsevier Ltd. All rights reserved
Author's personal copy Highly selective and potent l opioid ligands by unexpected substituent on morphine skeleton Wei Li a, , Yi-Min Tao b, , Yun Tang c , Xue-Jun Xu b , Jie Chen b , Wei Fu a , Xing-Hai Wang a , Bo Chao a , Wei Sheng a , Qiong Xie a , Zhui-Bai Qiu a,*, Jing-Gen Liu b,* aDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China c School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, China article info Article history: Received 10 April 2009 Revised 15 July 2009 Accepted 27 July 2009 Available online 29 July 2009 Keywords: l Opioid agonists Selective ligands Oripavines abstract Unexpected substituent on the well-known morphine skeleton is described to be account for highly selective and potent l opioid ligands, which is strongly connected to substituted aromatic groups on this omitted 8a-position. 2009 Elsevier Ltd. All rights reserved. Thebaine (Fig. 1) is a naturally occurred alkaloid isolated from opium. Though it bears much similar structure with morphine, thebaine is inactive as analgesic with very low affinities to opioid receptors.1 However, it could be converted to a variety of potent narcotics2 (e.g., Buprenorphine, Oxycodone) widely used in clinic through several organic transformations. And the Diels–Alder reaction of thebaine with dienophiles is obviously the most valuable one among these reactions, which leads to the discovery of extremely highly active analgesics than morphine.3 And due to less selective characters1 of these so-called oripavines yielded from the transformations of thebaine, the tritiated form of Diprenorphine and Etorphine has been used universally for opioid receptors. It is widely accepted that subtle differences in critical structural loci of bioactive compounds may result in great changes in biological responses. And these may provide useful information on drugreceptor interactions and on receptor characteristics.4 Since the greatly enhanced biological activities were suggested strongly to be linked with the substituent on C7 position which may be accommodated at the postulated lipophilic domain on the opioid receptor,5 it was desirable to investigate other cycloadducts of thebaine with dienophiles besides the well investigated 7a-adducts experimentally and theoretically.6 However, the 8a-adducts have been not considered seriously because not only are they not accessible through the cycloaddition of thebaine and dienophiles to date, but also significant decrease in analgesic potency7 and reduced affinities8 to opioid receptors have been observed in the known analogue in comparison to their main 7a-counterparts. In this Letter we reported unexpected 8a-adducts yielded from thebaine and styrenes which bear obviously different SARs (Structure–Activity Relationships) with other oripavines. And the substituent on the C8-position is strongly linked with l opioid agonistic activity and selectivity which has been omitted before. A straightforward synthetic strategy was developed (Scheme 1), and thebaine was preferably attacked by styrenes from the less bulky b face9 to afford 6a, 14a-endo-ethenotetrahydrothebaine. In addition to known 7a-adducts yielded as main products, unexpected by-products were separated in case of styrene, m-nitrostyrene and p-nitrostyrene. Follow-up works examined compound-5 by X-ray crystallography (Fig. 2, compound-5, CCDC 696689) and found it was a regioisomeric 8a-adduct in comparison to its main 7a-adduct (compound-4, CCDC 696688). Similar large deshielding effect to the proximity of the tertiary amine is observed for H-8b in 1 H NMR spectra of all regioisomeric adducts, as well as characteristic resonances of H7b upfield due to absence of substitution (Table 1). And normal 7b-adducts as were absent (Table 1). In the absence of the polarizing methoxy functionality at C-6 of thebaine, Diels–Alder addition to 3-buten-2-one can give a regioisomeric adduct in which the acetyl group is attached at C-8.7 And the Diels–Alder addition to styrenes may afford similar 0960-894X/$ - see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.07.119 * Corresponding authors. Tel.: +86 21 54237595; fax: +86 21 54237264 (Z.-B.Q.); tel.: +86 21 50807588 (J.-G.L.). E-mail addresses: zbqiu@shmu.edu.cn (Z.-B. Qiu), jgliu@mail.shcnc.ac.cn (J.-G. Liu). Both authors contribute equally to this work. Bioorganic & Medicinal Chemistry Letters 20 (2010) 418–421 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Author's personal copy W. Li et al./Bioorg Med. Chem. Lett. 20(2010)418-421 HcO OCH Morphine Etorphine Figure 1. The structures of thebaine, morphine, diprenorphine and etorphine. H3 =CH2 xylene, refle thebaine adducts adducts O-NO2 m-NO Scheme 1. The Diels-Alder reactions of thebaine and styrenes Sc19 Figure 2. X-ray crystal structures of compound-4(left)and-5(right). regioisomeric So-adducts, since these dienophiles are al heterotrimeric G protein, and has been used as a functional mea- of polarizing functionality in their structures which are sure for determination of potencies and efficacies of agonists. Thus, the agonistic activities of these compounds were determined by though other factors such as solvent, harsh conditions regulation of the binding of (5S]GTPyS(Table 3). Since most com effects, the trend of Diels-Alder reactions forwarded to main 7a- pounds have no undetectable affinities for 8-and k-opioid recep- adducts has not changed in all of these cases up to 10 HM Affinities of these compounds to opioid receptors were ompetitive inhibition of HJ (Table 2) Ligand regulation of the binding of BSS]GTPyS is one been shown in Table 2 and the agonistic activity of th he most widely used methods to measure receptor activation of compounds for u opioid receptors has been shown in Table 3
Author's personal copy regioisomeric 8a-adducts, since these dienophiles are also devoid of polarizing functionality in their structures which are different to other dienophiles such as 3-buten-2-one and acrylonitrile. Although other factors such as solvent, harsh conditions may take effects, the trend of Diels–Alder reactions forwarded to main 7aadducts has not changed in all of these cases. Affinities of these compounds to opioid receptors were determined by competitive inhibition of [3 H] diprenorphine binding (Table 2). Ligand regulation of the binding of [35S]GTPcS is one of the most widely used methods to measure receptor activation of heterotrimeric G protein, and has been used as a functional measure for determination of potencies and efficacies of agonists. Thus, the agonistic activities of these compounds were determined by regulation of the binding of [35S]GTPcS (Table 3). Since most compounds have no undetectable affinities for d- and j-opioid receptors at the concentrations up to 10 lM, only l opioid receptor was employed in the functional assays. The binding profiles of these compounds for three types of opioid receptors (l, d, j) have been shown in Table 2 and the agonistic activity of these compounds for l opioid receptors has been shown in Table 3. CH=CH2 R thebaine xylene, reflux N CH3 H3CO O H3CO 7α-adducts N CH3 H3CO O H3CO 8α-adducts + R R R= H o-NO2 m-NO2 p-NO2 1 3 4 6 2 5 7 Scheme 1. The Diels–Alder reactions of thebaine and styrenes. N O H3C H3CO OCH3 Thebaine N O H3C HO OH Morphine 7 8 Diprenorphine N HO O OCH3 C(CH3)2OH 7 8 Etorphine N CH3 HO O OCH3 OH CH3 CH2CH2CH3 Figure 1. The structures of thebaine, morphine, diprenorphine and etorphine. Figure 2. X-ray crystal structures of compound-4(left) and -5(right). W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 418–421 419
Author's personal copy W. Li et aL/ Bioorg. Med. Chem. Lett. 20(2010)418-421 Table 1 Isolated yields and characteristic resonances of H7B upfield and H8B downfield of Sa-adducts in comparison to 7a-adducts Compound entry 82-Adduct dH7B Ppm CH=CH 3.32-3. 3.18-3.14 3.40-3.34 2.25-220 71.7 3.16 3.0 2.242.17 4.41 The ratio of dienophile versus diene( thebaine) was 3: 1 (Isolated yield)% (e.g, compound-3, 4)almost abandoned activities against all opi- Affinity values for the binding of compounds to u, 8-and K-opioid receptors oid receptors. However, same substituents on Sa-position show different pharmacological profiles on H opioid receptor with en- K(nM) hanced affinities and selectivity which becomes even more signif icant when a nitro-group is introduced. And the Ki values of 10.000 compound-5 and compound-7 are 22.0+8.6 and 674.0+ 117.1 nM, respectively. Although compound-5 bears similar affini- ties with morphine, it is highly selective to H opioid receptor >10.000 while morphine reserves certain affinities to H and K-opioid recep- 6740±117.1 >10.000 tors. Follow-up functional assays demonstrated that both com- Morphine 69±1.3 1168±154 6.9+16.pounds bear similar potencies and efficacies with morphine with rom CHo cell ex the ECso value 3023±7.5( compound-5)and751.0± ompounds in the presence of 0.45 nM 95.0 nM(compound-7)and Maximal stimulation values of IH]diprenorphine as described under'Experimental section in Supplementary 221 t 2.8(compound-5 )and 248 +8.6(compound-7), respectively data. Data are expressed as Mean t SEM for at least three determinations performed Compound -5 is potent and highly selective u opioid agonist based on these pharmacological assays. The substituent on 8a-po- sition accounting for H opioid selectivity and activity of this compound is different from that on 7a-position producing non- 3 selective opioids although these two positions are sterically close Stimulation of ISGTPyS binding to membrane receptors by compounds to each other and this difference in sar results seemed to be con- ISS]GTPYS nected to the substituted aromatic substituent on 8o-position Maximum (% of basal) which may selectively increase the agonistic activities against H opioid receptor, but not 8-or K- ceptors. Further investiga- >10.000 tions on this specific position will be reported later. Morphine is a standard therapeutic agent of the treatment of 302.3±75 221±28 moderate-to-severe pain. However, its clinical use is greatly lim ited due to adverse side effects such as tolerance and dependence 7510±95.0 Morphine Lack of exclusive selectivity for individual receptor subtype might 123.5±30.5 209±159 be linked to its high potential to develop tolerance and depen- Assays were performed in membranes prepared from the cell expressing u dence. Thus, the findings of the present study may have potential opioid receptor with varying concentrations of compounds in the presence of importance for the development of new opioid analgesics with less the Mean t SEM for at least three experiments performed in triplicate. liability to develop tolerance and dependence. ND: not determinable, which means that the compounds nearly have no ability In conclusion, unexpected 8o-adducts from thebaine and dieno- BS]GTPS binding to membrane receptors(inactive philes were reported, and it was proposed that the appearance of these by-products may be connected to the structural features of dienophiles. Furthermore, compound-5 is potent and highly selec- Unlike typical oripavines (e.g, diprenorphine and etorphine) tive u opioid agonist, which is connected to the substituent with flexible s,on the 7a-position, 80-position on morphine skeleton. Further investigation on this tached directly to omitted position may be valuable to provide useful information ∝- adducts result in nities to all opioid receptors. for drug-receptor interactions since it is still in darkness for Furthermore, more bulky nitro-gi substituted analogues detailed interactions between opioid receptors and opioids, and
Author's personal copy Unlike typical oripavines (e.g., diprenorphine and etorphine) with flexible acyclic hydrophobic substituent on the 7a-position, more compact and rigid aromatic groups attached directly to 7a-adducts result in reduced affinities to all opioid receptors. Furthermore, more bulky nitro-group substituted analogues (e.g., compound-3, 4) almost abandoned activities against all opioid receptors. However, same substituents on 8a-position show different pharmacological profiles on l opioid receptor with enhanced affinities and selectivity which becomes even more significant when a nitro-group is introduced. And the Ki values of compound-5 and compound-7 are 22.0 ± 8.6 and 674.0 ± 117.1 nM, respectively. Although compound-5 bears similar affinities with morphine,10 it is highly selective to l opioid receptor while morphine reserves certain affinities to l and j-opioid receptors. Follow-up functional assays demonstrated that both compounds bear similar potencies and efficacies with morphine with the EC50 values to be 302.3 ± 7.5 (compound-5) and 751.0 ± 95.0 nM (compound-7) and Maximal stimulation values of 221 ± 2.8 (compound-5) and 248 ± 8.6 (compound-7), respectively. Compound-5 is potent and highly selective l opioid agonist based on these pharmacological assays. The substituent on 8a-position accounting for l opioid selectivity and activity of this compound is different from that on 7a-position producing nonselective opioids although these two positions are sterically close to each other. And this difference in SAR results seemed to be connected to the substituted aromatic substituent on 8a-position which may selectively increase the agonistic activities against l opioid receptor, but not d- or j-opioid receptors. Further investigations on this specific position will be reported later. Morphine is a standard therapeutic agent of the treatment of moderate-to-severe pain. However, its clinical use is greatly limited due to adverse side effects such as tolerance and dependence. Lack of exclusive selectivity for individual receptor subtype might be linked to its high potential to develop tolerance and dependence.11 Thus, the findings of the present study may have potential importance for the development of new opioid analgesics with less liability to develop tolerance and dependence. In conclusion, unexpected 8a-adducts from thebaine and dienophiles were reported, and it was proposed that the appearance of these by-products may be connected to the structural features of dienophiles. Furthermore, compound-5 is potent and highly selective l opioid agonist, which is connected to the substituent on the 8a-position on morphine skeleton. Further investigation on this omitted position may be valuable to provide useful information for drug-receptor interactions since it is still in darkness for detailed interactions between opioid receptors and opioids, and Table 1 Isolated yields and characteristic resonances of H7b upfield and H8b downfield of 8a-adducts in comparison to 7a-adducts Compound entry Dienophilea 7a-Adductb 8a-Adductb dH7b ppm dH8b ppm 1 CH=CH2 40.9 3.04 3.32–3.27 2 1.3 2.16 4.28 3 CH=CH2 NO2 83.6 3.71 3.46 4 CH=CH2 O2N 75.6 3.18–3.14 3.40–3.34 5 2.7 2.25–2.20 4.44 6 O2N CH=CH2 71.7 3.16 3.38 7 3.0 2.24–2.17 4.41 a The ratio of dienophile versus diene (thebaine) was 3:1. b (Isolated yield)%. Table 2 Affinity values for the binding of compounds to l-, d- and j-opioid receptorsa Ki (nM) l d j 1 >5000 >10,000 >10,000 2 >5000 >10,000 >10,000 4 >10,000 >10,000 >10,000 5 22.0 ± 8.6 >10,000 >10,000 6 >10,000 >10,000 >10,000 7 674.0 ± 117.1 >10,000 >10,000 Morphine 6.9 ± 1.3 116.8 ± 15.4 76.9 ± 16.3 a Membrane from CHO cell expressing l-, d- and j-opioid receptors were incubated with varying concentrations of compounds in the presence of 0.45 nM [ 3 H]diprenorphine as described under ‘Experimental section’ in Supplementary data. Data are expressed as Mean ± SEM for at least three determinations performed in triplicate. Table 3 Stimulation of [35S]GTPcS binding to membrane receptors by compoundsa [ 35S]GTPcS EC50 (nM) Maximum (% of basal) 1 >10,000 175 ± 6.0 2 >10,000 174 ± 5.2 4 NDb NDb 5 302.3 ± 7.5 221 ± 2.8 6 NDb NDb 7 751.0 ± 95.0 248 ± 8.6 Morphine 123.5 ± 30.5 209 ± 15.9 a Assays were performed in membranes prepared from the cell expressing l opioid receptor with varying concentrations of compounds in the presence of 0.1 nM [35S]GTPcS as described under ‘Material and methods’. Data are expressed as the Mean ± SEM for at least three experiments performed in triplicate. b ND: not determinable, which means that the compounds nearly have no ability to stimulate [35S]GTPcS binding to membrane receptors (inactive). 420 W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 418–421
Author's personal copy W. Li et al /Bioorg. Med. Chem. Lett. 20(2010)418-42 opioids with novel pharmacological profiles from the classical References and notes analgesic 1. Aldrich, J. V: Vigil-Cruz, S 3;vol.6,pp329- Acknowledgments 2. Synthesis of essential Drugs: Vardanyan, R.S., Hrul This work was supported by Doctoral Fund of the Ministry of 3. (a)Bently, K W: Hardy, D.C/Am.Chem.Soc. 1967.89,3267:(b)Be Education of China 20070246088, research project from Shanghai sitry and receptor: Casy, A F. Parfitt, R T- Eds: Plenum Press: Foundation 08ZR1401500: and was also supported by the Na- 4. Hole. H, D, In The Practice of Medicinal Chemistry: Wermuth,CG. Ed: Elsevier: tional Basic Research Program grant from the Ministry of Science 5. Loew, GH tz, D S.J. Med. Chem 1979, 22, 603. and Technology of China G2003CB515400, National Science Fund 6.(a)Coop, A: Grivas, K; Husbands, S: Lewis, J W Porter, J. for Distinguished Young Scholar from the National Natural Sci- nce Foundation of China 30425002, fund provided by Chinese chmidhammer, G. Russ. Org Chem. 2005, 41, 1132: ademy of Sciences(To J-G. Liu). We appreciate Miss Jing-mei no, K Y: Kim, K J. Bull. Korean Chem. Soc. 1991, 12. Wang and Professor Min-Qin Chen in Research Center for Analysis oung. C A. Chem Soc, C 1971. Measurement, Fudan University for their works on X-ra 158:(O Michne, w. F..Org. Chem. 7. Knipmeyer, LL; Rapoport, H J. Med. Chem. 1985, 28, 461 8. Maat, L: Woudenberg. R H; Meuzelaar, G. -: Linders, ] T M. Bioorg. Med. Chem Supplementary data 10. Neilan, C L, Husbands, S. M: Breeden S. Aceto. M. D: Lewis, J. w Woods, J. H: Traynor, J. R Eur. PharmacoL 2004, 499, 107. applementary data associated with this article can be found, 11. (a)Abdelhamid, E. E: Sultana, M. Portoghese, P S: Takemori, AE. J. Pharmacol. Exp Ther. 1991, 258, 299: (b)Miyamoto, Y. Portoghese, P S: Takemori, A EJ. n. at doi:10.1016bmcl2009.07.119 Pharmacol. Exp Ther. 1993. 265, 1325
Author's personal copy opioids with novel pharmacological profiles from the classical structure of analgesics. Acknowledgments This work was supported by Doctoral Fund of the Ministry of Education of China 20070246088, research project from Shanghai Municipal Health Bureau 2007089, and Shanghai Natural Science Foundation 08ZR1401500; and was also supported by the National Basic Research Program grant from the Ministry of Science and Technology of China G2003CB515400, National Science Fund for Distinguished Young Scholar from the National Natural Science Foundation of China 30425002, fund provided by Chinese Academy of Sciences (To J.-G. Liu). We appreciate Miss Jing-mei Wang and Professor Min-Qin Chen in Research Center for Analysis & Measurement, Fudan University for their works on X-ray crystallography. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.bmcl.2009.07.119. References and notes 1. Aldrich, J. V.; Vigil-Cruz, S. C.. In Burger’s Medicinal Chemistry & Drug Discovery; Abraham, D. J., Ed.; JohnWiley and Sons Inc.: New York, 2003; Vol. 6, pp 329–482. 2. Synthesis of Essential Drugs; Vardanyan, R. S., Hruby, V. J., Eds.; Elsevier, 2006; pp 19–55. 3. (a) Bently, K. W.; Hardy, D. G. J. Am. Chem. Soc. 1967, 89, 3267; (b) Bently, K. W.; Hardy, D. G.; Meek, B. J. Am. Chem. Soc. 1967, 89, 3273; (c)Opioid analgesics: Chemsitry and receptor; Casy, A. F., Parfitt, R. T., Eds.; Plenum Press: New York and London, 1986. 4. Höltje, H. D. In The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Elsevier: London, 2003; pp 387–401. 5. Loew, G. H.; Berkowitz, D. S. J. Med. Chem. 1979, 22, 603. 6. (a) Coop, A.; Grivas, K.; Husbands, S.; Lewis, J. W.; Porter, J. Tetrahedron Lett. 1995, 36, 1689; (b) Baas, J. M. A.; Woudenberg, R. H.; Maat, L. Liebigs Ann. Recl. 1997, 13; (c) Shults, E. E.; Shakirov, M. M.; Tolstikov, G. A.; Kalinin, V. N.; Schmidhammer, G. Russ. J. Org. Chem. 2005, 41, 1132; (d) Jeong, I. H.; Kim, Y. S.; Cho, K. Y.; Kim, K. J. Bull. Korean Chem. Soc. 1991, 12, 125; (e) Lewis, J. W.; Readhead, M. J.; Selby, I. A.; Smith, A. C. B.; Young, C. A. J. Chem. Soc., C 1971, 1158; (f) Michne, W. F. J. Org. Chem. 1976, 41, 894. 7. Knipmeyer, L. L.; Rapoport, H. J. Med. Chem. 1985, 28, 461. 8. Maat, L.; Woudenberg, R. H.; Meuzelaar, G. J.; Linders, J. T. M. Bioorg. Med. Chem. 1999, 7, 529. 9. Linders, J. T. M.; Maat, L. Bull. Soc. Chim. Belg. 1989, 98, 265. 10. Neilan, C. L.; Husbands, S. M.; Breeden, S.; Ko, M. C.; Aceto, M. D.; Lewis, J. W.; Woods, J. H.; Traynor, J. R. Eur. J. Pharmacol. 2004, 499, 107. 11. (a) Abdelhamid, E. E.; Sultana, M.; Portoghese, P. S.; Takemori, A. E. J. Pharmacol. Exp. Ther. 1991, 258, 299; (b) Miyamoto, Y.; Portoghese, P. S.; Takemori, A. E. J. Pharmacol. Exp. Ther. 1993, 265, 1325. W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 418–421 421
