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AAPS J. 2006 September; 8(3): E450–E460.
Published online 2006 July 14. doi:  10.1208/aapsj080353
PMCID: PMC1764851

New paradigms and tools in drug design for pain and addiction


New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at μ and σ opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in g-protein coupled receptors (GPCRs) as illustrated by the δ opioid receptor.

Keywords: drug design, neuropathic pain, bifunctional ligands, plasmon waveguide resonance spectroscopy, GPCRs, opioid receptors, cholecystokinin receptors

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Hruby VJ. Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov. 2002;1:847–858. doi: 10.1038/nrd939. [PubMed] [Cross Ref]
2. Ossipov MH, Lai J, Porreca F. Mechanisms of experimental neuropathic pain: Integration from animal models. In: McMahon S, Koltzenburg M, editors. Wall and Melzack’s Textbook of Pain. 5th ed. New York, NY: Elsevier; 2005. pp. 929–946.
3. Ossipov MH, Porreca F. Challenges in the development of novel treatment strategies for neuropathic pain. NeuroRx. 2005;2:650–661. doi: 10.1602/neurorx.2.4.650. [PubMed] [Cross Ref]
4. Vera-Portocarrero LP, Zhang ET, Ossipov MH, et al. Descending facilitation from the rostral ventromedial medulla maintains nerve injury-indued central sensitization.Neuroscience. In press. [PubMed]
5. Ossipov MH, Porreca F. Descending modulation of pain. In: Merskey H, Loeser JD, Dubner R, editors. The Paths of Pain 1975–2005. Seattle, WA: IASP Press; 2005. pp. 117–130.
6. Xie JY, Herman SD, Stiller CO, et al. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J Neurosci. 2005;25:409–416. doi: 10.1523/JNEUROSCI.4054-04.2005. [PubMed] [Cross Ref]
7. King T, Ossipov MH, Vanderah TW, Porreca F, Lai J. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals. 2005;14:194–205. doi: 10.1159/000087658. [PubMed] [Cross Ref]
8. Heinricher MM, Neubert MJ. Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiol. 2004;92:1982–1989. doi: 10.1152/jn.00411.2004. [PubMed] [Cross Ref]
9. Wilcox GL, Stone LS, Ossipov MH, Lai J, Porreca F. Pharmacology of pain and analgesia. In: Pappagallo M, editor. The Neurologic Basic of Pain. New York, NY: McGraw-Hill; 2004. pp. 31–52.
10. Hruby VJ, Meyer J-P. Chemical synthesis of peptides. In: Hecht SM, editor. Bioorganic Chemistry: Peptides and Proteins. New York, NY: Oxford University Press; 1998. pp. 27–64.
11. Misicka A, Lipkowski AW, Horvath R, et al. Topographical requirements for ϕ opioid ligands: common structural features of dermenkephalin and deltorphin. Life Sci. 1992;51:1025–1032. doi: 10.1016/0024-3205(92)90501-F. [PubMed] [Cross Ref]
12. Kramer TH, Davis P, Hruby VJ, Burks TF, Porreca F. In vitro potency, affinity and agonist efficacy of highly selective ϕ opioid receptor ligands. J Pharmacol Exp Ther. 1993;266:577–584. [PubMed]
13. Salamon Z, Macleod HA, Tollin G. Coupled plasmon-waveguide resonators: a new spectroscopic tool for probing proteolipid film structure and properties. Biophys J. 1997;73:2791–2797. doi: 10.1016/S0006-3495(97)78308-5. [PubMed] [Cross Ref]
14. Salamon Z, Tollin G. Plasm on resonance spectroscopy: probing molecular interactions at surfaces and interfaces. Spectroscopy. 2005;15:161–175.
15. Tollin G, Salamon Z, Hruby VJ. Techniques: plasmon-waveguide resonance (PWR) spectroscopy as a tool to study ligand-GPCR interactions. Trends Pharmacol Sci. 2003;24:655–659. doi: 10.1016/ [PubMed] [Cross Ref]
16. Salamon Z, Cowell S, Varga E, Yamamura HI, Hruby VJ, Tollin G. Plasmon resonance studies of agonist/antagonist binding to the human ϕ-opioid receptor: new structural insights into receptor-ligand interactions. Biophys J. 2000;79:2463–2474. [PubMed]
17. Alves ID, Salamon Z, Varga E, Yamamura HI, Tollin G, Hruby VJ. Direct observation of G-protein binding to the human ϕ-opioid receptor using plasmon-waveguide resonance spectroscopy. J Biol Chem. 2003;278:48890–48897. doi: 10.1074/jbc.M306866200. [PubMed] [Cross Ref]
18. Slaninová J, Knapp RJ, Wu J, et al. Opioid receptor binding properties of analgesic analogues of cholecystokinin octapeptide. Eur J Pharmacol. 1991;200:195–198. doi: 10.1016/0014-2999(91)90688-M. [PubMed] [Cross Ref]
19. Mosberg HI, Hurst R, Hruby VJ, et al. Bis-penicillamine enkephalins possess highly improved specificity toward ϕ opioid receptors. Proc Natl Acad Sci USA. 1983;80:5871–5874. doi: 10.1073/pnas.80.19.5871. [PubMed] [Cross Ref]
20. Hruby VJ, Fang SN, Kramer TH. Analogues of cholecystokinin26–33 selective for B-type CCK receptors possess ϕ opioid receptor agonist activity in vitro and in vivo: Evidence for similarities in CCK-B and ϕ opioid receptor requirements. In: Hodges RS, Smith JA, editors. Peptides: Chemistry, Structure and Biology; Leiden, The Netherlands: ESCOM Publishers; 1994. pp. 669–671.
21. Nikiforovich GV, Hruby VJ, Prakash O, Gehrig CA. Topographical requirements for ϕ-selective opioid peptides. Biopolymers. 1991;31:941–955. doi: 10.1002/bip.360310804. [PubMed] [Cross Ref]
22. Hruby VJ, Fang SN, Knapp R, Kazmierski WM, Lui GK, Yamamura HI. Cholecystokinin analogues with high affinity and selectivity for brain membrane receptors. Int J Pept Protein Res. 1990;35:566–573. [PubMed]
23. Hruby VJ. Conformational restrictions of biologically active peptides via amino acid side chain groups. Life Sci. 1982;31:189–199. doi: 10.1016/0024-3205(82)90578-1. [PubMed] [Cross Ref]
24. Hruby VJ, Al-Obeidi F, Kazmierski WM. Emerging approaches in the molecular design of receptor selective peptide ligands: conformational, topographical and dynamic considerations. Biochem J. 1990;268:249–262. [PubMed]
25. Bartosz-Bechowski H, Davis P, Slaninova J, et al. Cyclic enkephalin analogues that are hybrids of DPDPE-related peptides and Met-enkephalin-Arg-Gly-Leu: prohormone analogues that retain good potency and selectivity for ϕ opioid receptors. J Pept Res. 1999;53:329–336. doi: 10.1034/j.1399-3011.1999.00033.x. [PubMed] [Cross Ref]
26. Hruby VJ, Bartosz-Bechowski H, Davis P, et al. Cyclic enkephalin analogues with exceptional potency and selectivity for ϕ-opioid receptors. J Med Chem. 1997;40:3957–3962. doi: 10.1021/jm9704762. [PubMed] [Cross Ref]
27. Alves ID, Cowell SM, Salamon Z, Devanathan S, Tollin G, Hruby VJ. Different structural states of the proteolipid membrane are produced by ligand binding to the human ϕ-opioid receptor as shown by plasmonwaveguide resonance spectroscopy. Mol Pharmacol. 2004;65:1248–1257. doi: 10.1124/mol.65.5.1248. [PubMed] [Cross Ref]
28. Hosohata Y, Varga EV, Stropova D, et al. Mutation W284L of the human ϕ opioid receptor reveals agonist specific conformational mechanisms of G-protein activation. Life Sci. 2001;68:2233–2242. doi: 10.1016/S0024-3205(01)01011-6. [PubMed] [Cross Ref]
29. Alves ID, Salamon Z, Varga E, Yamamura HI, Tollin G, Hruby VJ. Direct observation of G-protein binding to the human ϕ-opioid receptor using plasmon-waveguide resonance spectroscopy. J Biol Chem. 2003;278:48890–48897. doi: 10.1074/jbc.M306866200. [PubMed] [Cross Ref]
30. Alves ID, Ciano KA, Boguslavsky V, et al. Selectivity, cooperativity, and reciprocity in the interactions between the ϕ-opioid receptor, its ligands, and G-proteins. J Biol Chem. 2004;279:44673–44682. doi: 10.1074/jbc.M404713200. [PubMed] [Cross Ref]

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