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. 2006 Mar 10;8(1):E126–E137. doi: 10.1208/aapsj080115

Molecular recognition of opioid receptor ligands

Brian E Kane 1, Bengt Svensson 1, David M Ferguson 1,✉
PMCID: PMC2751431  PMID: 16584119

Abstract

The cloning of the opioid receptors and subsequent use of recombinant DNA technology have led to many new insights into ligand binding. Instead of focusing on the structural features that lead to increased affinity and selectivity, researchers are now able to focus on why these features are important. Site-directed mutagenesis and chimeric data have often been at the forefront in answering these questions. Herein, we survey pharmacophores of several opioid ligands in an effort to understand the structural requirements for ligand binding and selectivity. Models are presented and compared to illustrate key sites of recognition for both opiate and nonopiate ligands. The results indicate that different ligand classes may recognize different sites within the receptor, suggesting that multiple epitopes may exist for ligand binding and selectivity.

Keywords: Opioid, structure-function, pharmacophore, mutagenesis, chimeric

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References

  • 1.Haeyoung K, Raynor K, Reisine T. Amino acids in the cloned mouse kappa receptor that are necessary for high affinity agonist binding but not antagonist binding. Regul Pept. 1994;54:155–156. doi: 10.1016/0167-0115(94)90437-5. [DOI] [Google Scholar]
  • 2.Meng F, Hoversten MT, Thompson RC, Taylor L, Watson SJ, Akil H. A chimeric study of the molecular basis of affinity and selectivity of the κ and the δ opioid receptors: potential role of extracellular domains. J Biol Chem. 1995;270:12730–12736. doi: 10.1074/jbc.270.24.14383. [DOI] [PubMed] [Google Scholar]
  • 3.Xue JC, Chen C, Zhu J, et al. The third extracellular loop of the μ opioid receptor is important for agonist selectivity. J Biol Chem. 1995;270:12977–12979. [PubMed] [Google Scholar]
  • 4.Meng F, Ueda Y, Hoversten MT, et al. Mapping the receptor domains critical for the binding selectivity of delta-opioid receptor ligands. Eur J Pharmacol. 1996;311:285–292. doi: 10.1016/0014-2999(96)00431-1. [DOI] [PubMed] [Google Scholar]
  • 5.Wang JB, Johnson PS, Wu JM, Wang WF, Uhl GR. Human κ opiate receptor second extracellular loop elevates dynorphin's affinity for human μ/κ chimeras. J Biol Chem. 1994;269:25966–25969. [PubMed] [Google Scholar]
  • 6.Teschemacher H, Opheim KE, Cox BM, Goldstein A. Peptidelike substance from pituitary that acts like morphine, I: isolation. Life Sci. 1975;16:1771–1775. doi: 10.1016/0024-3205(75)90271-4. [DOI] [PubMed] [Google Scholar]
  • 7.Strader CD, Sigal IS, Dixon RA. Structural basis of β-adrenergic receptor function. FASEB J. 1989;3:1825–1832. doi: 10.1096/fasebj.3.7.2541037. [DOI] [PubMed] [Google Scholar]
  • 8.Hibert MF, Trumpp-Kallmeyer S, Bruinvels A, Hoflack J. Three-dimensional models of neurotransmitter G-binding protein-coupled receptors. Mol Pharmacol. 1991;40:8–15. [PubMed] [Google Scholar]
  • 9.Trumpp-Kallmeyer S, Hoflack J, Bruinvels A, Hibert M. Modeling of G-protein-coupled receptors: application to dopamine, adrenaline, serotonin, acetylcholine, and mammalian opsin receptors. J Med Chem. 1992;35:3448–3462. doi: 10.1021/jm00097a002. [DOI] [PubMed] [Google Scholar]
  • 10.Baldwin JM. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 1993;12:1693–1703. doi: 10.1002/j.1460-2075.1993.tb05814.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Strader CD, Sigal IS, Candelore MR, Rands E, Hill WS, Dixon RAF. Conserved aspartic acid residues 79 and 113 of the β-adrenergic receptor have different roles in receptor function. J Biol Chem. 1988;263:10267–10271. [PubMed] [Google Scholar]
  • 12.Strader CD, Candelore MR, Hill WS, Sigal IS, Dixon RA. Identification of two serine residues involved in agonist activation of the β-adrenergic receptor. J Biol Chem. 1989;264:13572–13578. [PubMed] [Google Scholar]
  • 13.Lenz GR, Evans SM, Walters DE, Hopfinger AJ. Opiates. Orlando, FL: Academic Press; 1986. [Google Scholar]
  • 14.Surratt CK, Johnson PS, Moriwaki A, et al. Mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem. 1994;269:20548–20553. [PubMed] [Google Scholar]
  • 15.Spivak CE, Beglan CL, Seidleck BK, et al. Naloxone activation of μ-opioid receptors mutated at a histidine residue lining the opioid binding cavity. Mol Pharmacol. 1997;52:983–992. doi: 10.1124/mol.52.6.983. [DOI] [PubMed] [Google Scholar]
  • 16.Schwyzer R, Eberle A. On the molecular mechanism of α-MSH receptor interactions. Front Horm Res. 1977;4:18–25. [PubMed] [Google Scholar]
  • 17.Portoghese PS, Sultana M, Takemori AE. Design of peptidomimetic δ opioid receptor antagonists using the message-address concept. J Med Chem. 1990;33:1714–1720. doi: 10.1021/jm00168a028. [DOI] [PubMed] [Google Scholar]
  • 18.Resnick RB, Volavka J, Freedman AM, Thomas M. Studies of EN-1639A (naltrexone): a new narcotic antagonist. Am J Psychiatry. 1974;131:646–650. doi: 10.1176/ajp.131.6.646. [DOI] [PubMed] [Google Scholar]
  • 19.Portoghese PS, Sultana M, Takemori AE. Naltrindole: a highly selective and potent non-peptide delta opioid receptor antagonist. Eur J Pharmacol. 1988;146:185–186. doi: 10.1016/0014-2999(88)90502-X. [DOI] [PubMed] [Google Scholar]
  • 20.Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Mutational evidence for a common κ antagonist binding pocket in the wild-type κ and mutant μ[K303E] opioid receptors. J Med Chem. 1998;41:4911–4914. doi: 10.1021/jm9805182. [DOI] [PubMed] [Google Scholar]
  • 21.Magnan J, Paterson SJ, Tavani A, Kosterlitz HW. The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn Schmiedebergs Arch Pharmacol. 1982;319:197–205. doi: 10.1007/BF00495865. [DOI] [PubMed] [Google Scholar]
  • 22.Szmuszkovicz J, Von Voightlander PF. Benzeneacetamide amines: structurally novel non-μ-opioids. J Med Chem. 1982;25:1125–1126. doi: 10.1021/jm00352a005. [DOI] [PubMed] [Google Scholar]
  • 23.Lahti RA, Mickelson MM, McCall JM, Von Voigtlander PF. [3H]U-69593 a highly selective ligand for the opioid kappa receptor. Eur J Pharmacol. 1985;109:281–284. doi: 10.1016/0014-2999(85)90431-5. [DOI] [PubMed] [Google Scholar]
  • 24.Subramanian G, Paterlini MG, Portoghese PS, Ferguson DM. Molecular docking reveals a novel binding site model for fentanyl at the μ-opioid receptor. J Med Chem. 2000;43:381–391. doi: 10.1021/jm9903702. [DOI] [PubMed] [Google Scholar]
  • 25.Xu H, Lu YF, Partilla JS, et al. Opioid peptide receptor studies, 11: involvement of Tyr149, Trp318 and His319 of the rat μ-opioid receptor in binding of μ-selective ligands. Synapse. 1999;32:23–28. doi: 10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  • 26.Jiang HL, Huang XQ, Rong SB, et al. Theoretical studies on opioid receptors and ligands, I: molecular modeling and QSAR studies on the interaction mechanism of fentanyl analogs binding to μ-opioid receptor. Int J Quantum Chem. 2000;78:285–293. doi: 10.1002/(SICI)1097-461X(2000)78:4<285::AID-QUA11>3.0.CO;2-I. [DOI] [Google Scholar]
  • 27.Subramanian G, Paterlini MG, Larson DL, Portoghese PS, Ferguson DM. Conformational analysis and automated receptor docking of selective arylacetamide-based κ-opioid agonists. J Med Chem. 1998;41:4777–4789. doi: 10.1021/jm9803166. [DOI] [PubMed] [Google Scholar]
  • 28.Lavecchia A, Greco G, Novellino E, Vittorio F, Ronsisvalle G. Modeling of κ-opioid receptor/agonists interactions using pharmacophore-based and docking simulations. J Med Chem. 2000;43:2124–2134. doi: 10.1021/jm991161k. [DOI] [PubMed] [Google Scholar]
  • 29.Cappelli A, Anzini M, Vomero S, et al. Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for κ-opioid receptors. J Med Chem. 1996;39:860–872. doi: 10.1021/jm950423p. [DOI] [PubMed] [Google Scholar]
  • 30.Pogozheva ID, Lomize AL, Mosberg HI. Opioid receptor three-dimensional structures from distance geometry calculations with hydrogen bonding constraints. Biophys J. 1998;75:612–634. doi: 10.1016/S0006-3495(98)77552-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Knapp RJ, Malatynska E, Collins N, et al. Molecular biology and pharmacology of cloned opioid receptors. FASEB J. 1995;9:516–525. doi: 10.1096/fasebj.9.7.7737460. [DOI] [PubMed] [Google Scholar]
  • 32.Jiang Q, Takemori AE, Sultana M, et al. Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5′-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther. 1991;257:1069–1075. [PubMed] [Google Scholar]
  • 33.Sofuoglu M, Portoghese PS, Takemori AE. 7-Benzylidenenaltrexone (BTNX): a selective Δ1 opioid receptor antagonist in the mouse spinal cord. Life Sci. 1993;52:769–775. doi: 10.1016/0024-3205(93)90240-4. [DOI] [PubMed] [Google Scholar]
  • 34.Zaki PA, Bilsky EJ, Vanderah TW, Lai J, Evans CJ, Porreca F. Opioid receptor types and subtypes: the δ receptor as a model. Annu Rev Pharmacol Toxicol. 1996;36:379–401. doi: 10.1146/annurev.pa.36.040196.002115. [DOI] [PubMed] [Google Scholar]
  • 35.Stenkamp RE, Filipek S, Driessen CA, Teller DC, Palczewski K. Crystal structure of rhodopsin: a template for cone visual pigments and other G protein-coupled receptors. Biochim Biophys Acta. 2002;1565:168–182. doi: 10.1016/S0005-2736(02)00567-9. [DOI] [PubMed] [Google Scholar]
  • 36.Filipek S, Teller DC, Palczewski K, Stenkamp R. The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors. Annu Rev Biophys Biomol Struct. 2003;32:375–397. doi: 10.1146/annurev.biophys.32.110601.142520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Metzger TG, Paterlini MG, Portoghese PS, Ferguson DM. Application of the message-address concept of the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models. Neurochem Res. 1996;21:1287–1294. doi: 10.1007/BF02532369. [DOI] [PubMed] [Google Scholar]
  • 38.Alkorta I, Loew GH. A 3D model of the δ opioid receptor and ligand-receptor complexes. Protein Eng. 1996;9:573–583. doi: 10.1093/protein/9.7.573. [DOI] [PubMed] [Google Scholar]
  • 39.Strahs D, Weinstein H. Comparative modeling and molecular dynamics studies of the δ, κ and μ opioid receptors. Protein Eng. 1997;10:1019–1038. doi: 10.1093/protein/10.9.1019. [DOI] [PubMed] [Google Scholar]
  • 40.Meng EC, Shoichet BK, Kuntz ID. Automated docking with grid-based energy evaluation. J Comput Chem. 1992;13:505–524. doi: 10.1002/jcc.540130412. [DOI] [Google Scholar]
  • 41.Blumberg H, Dayton HB, Wolf PS. Counteraction of narcotic antagonist analgesics by the narcotic antagonist naloxone. Proc Soc Exp Biol Med. 1966;123:755–758. doi: 10.3181/00379727-123-31595. [DOI] [PubMed] [Google Scholar]
  • 42.Pasternak GW, Snyder SH. Opiate receptor binding: enzymic treatments that discriminate between agonist and antagonist interactions. Mol Pharmacol. 1975;11:478–484. [Google Scholar]
  • 43.Beckett AH, Casy AF. Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol. 1954;6:986–1001. doi: 10.1111/j.2042-7158.1954.tb11033.x. [DOI] [PubMed] [Google Scholar]
  • 44.Attwood TK, Findlay JBC. Fingerprinting G-protein-coupled receptors. Protein Eng. 1994;7:195–203. doi: 10.1093/protein/7.2.195. [DOI] [PubMed] [Google Scholar]
  • 45.Befort K, Tabbara L, Kling D, Maigret B, Kieffer BL. Role of aromatic transmembrane residues on the δ-opioid receptor in ligand recognition. J Biol Chem. 1996;271:10161–10168. doi: 10.1074/jbc.271.17.10161. [DOI] [PubMed] [Google Scholar]
  • 46.Hjorth SA, Thirstrup K, Grandy DK, Schwartz TW. Analysis of selective binding epitopes for the κ-opioid receptor antagonist nor-binaltorphimine. Mol Pharmacol. 1995;47:1089–1094. [PubMed] [Google Scholar]
  • 47.Valiquette M, Vu HK, Yue SY, Wahlestedt C, Walker P. Involvement of Trp-284, Val-296, and Val-297 of the human δ-opioid receptor in binding of δ-selective ligands. J Biol Chem. 1996;271:18789–18796. doi: 10.1074/jbc.271.31.18789. [DOI] [PubMed] [Google Scholar]
  • 48.Portoghese AS, Lipkowski AW, Takemori AE. Bimorphinans as highly selective, potent κ opioid receptor antagonists. J Med Chem. 1987;30:238–239. doi: 10.1021/jm00385a002. [DOI] [PubMed] [Google Scholar]
  • 49.Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS. Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the ‘address’ recognition locus. J Med Chem. 2001;44:857–862. doi: 10.1021/jm000381r. [DOI] [PubMed] [Google Scholar]
  • 50.Portoghese PS, Moe ST, Takemori AE. A selective θ1 opioid receptor agonist derived from oxymorphone. Evidence for separate recognition sites for θ1 opioid receptor agonists and antagonists. J Med Chem. 1993;36:2572–2574. doi: 10.1021/jm00069a017. [DOI] [PubMed] [Google Scholar]
  • 51.Bonner G, Meng F, Akil H. Selectivity of μ-opioid receptor determined by interfacial residues near third extracellular loop. Eur J Pharmacol. 2000;403:37–44. doi: 10.1016/S0014-2999(00)00578-1. [DOI] [PubMed] [Google Scholar]
  • 52.Pil J, Tytgat J. The role of the hydrophilic Asn230 residue of the μ-opioid receptor in the potency of various opioid agonists. Br J Pharmacol. 2001;134:496–506. doi: 10.1038/sj.bjp.0704263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Kanematsu K, Sagara T. An approach to the rational design of opioid receptor ligands: non-narcotic κ-opioid receptor ligand KT-95 free from euphoria and/or dysphoria. Curr Med Chem CNS Agents. 2001;1:1–25. doi: 10.2174/1568011013354859. [DOI] [Google Scholar]
  • 54.Liu-Chen LY, Li SX, Tallarida RJ. Studies on kinetics of [3H]β-funaltrexamine binding to μ opioid receptor. Mol Pharmacol. 1990;37:243–250. [PubMed] [Google Scholar]
  • 55.Chen C, Yin J, Riel JK, et al. Determination of the amino acid residue involved in [3H]β-funaltrexamine covalent binding in the cloned rat μ-opioid receptor. J Biol Chem. 1996;271:21422–21429. doi: 10.1074/jbc.271.35.21422. [DOI] [PubMed] [Google Scholar]
  • 56.Calderon SN, Rothman RB, Porreca F, et al. Probes for narcotic receptor mediated phenomena, 19: synthesis of (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide δ opioid receptor agonist. J Med Chem. 1994;37:2125–2128. doi: 10.1021/jm00040a002. [DOI] [PubMed] [Google Scholar]
  • 57.Liao S, Alfaro-Lopez J, Shenderovich MD, et al. De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the delta-opioid receptor. J Med Chem. 1998;41:4767–4776. doi: 10.1021/jm980374r. [DOI] [PubMed] [Google Scholar]
  • 58.Coop A, Jacobson AE. The LMC delta opioid recognition pharmacophore: comparison of SNC80 and oxymorphindole. Bioorg Med Chem Lett. 1999;9:357–362. doi: 10.1016/S0960-894X(98)00745-8. [DOI] [PubMed] [Google Scholar]
  • 59.Bernard D, Coop A, MacKerell AD. 2D conformationally sampled pharmacophore: a ligand-based pharmacophore to differentiate delta opioid agonists from antagonists. J Am Chem Soc. 2003;125:3101–3107. doi: 10.1021/ja027644m. [DOI] [PubMed] [Google Scholar]
  • 60.Carson JR, Carmosin FJ, Fitzpatrick LJ, Reitz AB, Jetter MC, inventors. 4-[aryl(piperidin-4-yl)]aminobenzamides. US patent 6 436 959. December 23, 1998.
  • 61.Wei ZY, Brown W, Takasaki B, et al. N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent δ opioid receptor agonist with oral bioavailability and its analogues. J Med Chem. 2000;43:3895–3905. doi: 10.1021/jm000229p. [DOI] [PubMed] [Google Scholar]
  • 62.Knapp RJ, Santoro G, De Leon IA, et al. Structure-activity relationships for SNC80 and related compounds at cloned human delta and mu opioid receptors. J Pharmacol Exp Ther. 1996;277:1284–1291. [PubMed] [Google Scholar]
  • 63.Calderon SN, Coop A. SNC 80 and related δ opioid agonists. Curr Pharm Des. 2004;10:733–742. doi: 10.2174/1381612043453054. [DOI] [PubMed] [Google Scholar]
  • 64.Podlogar BL, Poda GI, Demeter DA, et al. Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the δ-opioid receptor: a combined 3D-QSAR and ligand docking study. Drug Des Discov. 2000;17:34–50. [PubMed] [Google Scholar]
  • 65.Dondio G, Ronzoni S, Eggleston DS, et al. Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective δ opioid agonists, based on an extension of the message-address concept. J Med Chem. 1997;40:3192–3198. doi: 10.1021/jm9608218. [DOI] [PubMed] [Google Scholar]
  • 66.Dondio G, Ronzoni S, Petrillo P, Desjarlais RL, Raveglia LF. Pyrrolooctahydroisoquinolines as potent and selective δ opioid receptor ligands: SAR analysis and docking studies. Bioorg Med Chem Lett. 1997;7:2967–2972. doi: 10.1016/S0960-894X(97)10119-6. [DOI] [Google Scholar]
  • 67.Casy AF, Parfitt RT. Opioid Analgesics: Chemistry and Receptors. New York, NY: Plenum Press; 1986. [Google Scholar]
  • 68.Subramanian G, Ferguson DM. Conformational landscape of selective μ-opioid agonists in gas phase and in aqueous solution: the fentanyl series. Drug Des Discov. 2000;17:55–67. [PubMed] [Google Scholar]
  • 69.Cometta-Morini C, Loew GH. Development of a conformational search strategy for flexible ligands: a study of the potent mu-selective opioid analgesic fentanyl. J Comput Aided Mol Des. 1991;5:335–356. doi: 10.1007/BF00126667. [DOI] [PubMed] [Google Scholar]
  • 70.Brandt W, Barth A, Holtje HD. A new consistent model explaining structure (conformation)-activity relationships of opiates with μ-selectivity. Drug Des Discov. 1993;10:257–283. [PubMed] [Google Scholar]
  • 71.Tang Y, Chen KX, Jiang HL, Wang ZX, Ji RY, Chi ZQ. Molecular modeling of μ opioid receptor and its interaction with ohmefentanyl. Zhongguo Yao Li Xue Bao. 1996;17:156–160. [PubMed] [Google Scholar]
  • 72.Xu H, Lu YF, Partilla JS, et al. Opioid peptide receptor studies, 11: involvement of Tyr149, Trp318 and His319 of the rat μ-opioid receptor in binding of μ-selective ligands. Synapse. 1999;32:23–28. doi: 10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  • 73.Winter CA, Orahovats PD, Lehman EG. Analgesic activity and morphine antagonism of compounds related to nalorphine. Arch Int Pharmacodyn Ther. 1957;110:186–202. [PubMed] [Google Scholar]
  • 74.Hunter JC, Leighton GE, Meecham KG, et al. CI-977, a novel and selective agonist for the κ-opioid receptor. Br J Pharmacol. 1990;101:183–189. doi: 10.1111/j.1476-5381.1990.tb12110.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Rees DC. Chemical structures and biological activities of non-peptide selective kappa opioid ligands. Prog Med Chem. 1992;29:109–139. doi: 10.1016/s0079-6468(08)70006-7. [DOI] [PubMed] [Google Scholar]
  • 76.Froimowitz M, DiMeglio CM, Makriyannis A. Conformational preferences of the κ-selective opioid agonist U50488. A combined molecular mechanics and nuclear magnetic resonance study. J Med Chem. 1992;35:3085–3094. doi: 10.1021/jm00095a001. [DOI] [PubMed] [Google Scholar]
  • 77.Higginbottom M, Nolan W, O'Toole J, Ratcliffe GS, Rees DC, Roberts E. The design and synthesis of κ opioid ligands based on a binding model for κ agonists. Bioorg Med Chem Lett. 1993;3:841–846. doi: 10.1016/S0960-894X(00)80677-0. [DOI] [Google Scholar]
  • 78.Rajagopalan P, Scribner RM, Pennev P, et al. Dup 747: sar study. Bioorg Med Chem Lett. 1992;2:721–726. doi: 10.1016/S0960-894X(00)80399-6. [DOI] [Google Scholar]
  • 79.Thirstrup K, Hjorth SA, Schwartz TW. Investigation of the binding pocket in the kappa opioid receptor by a combination of alanine substitutions and steric hindrance mutagenesis. Poster M30. 27th Meeting of the International Narcotics Research Conference; July 21–26, 1996; Long Beach, CA.

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