Opioid Ligand Binding Site

There are no x-ray crystal structures reported for any opioid receptor, and most modeling work has been based on the crystal structure of rhodopsin. Many groups have attempted to find the specific binding site through homology modeling, molecular dynamics, site-directed mutagenesis, chimeric receptors, truncated receptors, and SAR studies. As of yet, no definitive model of the ligand-binding site is available. The opioid-binding site for all four opioid receptors is believed to be an inner cavity formed by conserved residues on TM helices TM3, TM4, TM5, TM6, and TM7.33 35 Not all groups agree that the binding pocket is formed via TM domains; some evidence suggest that the amino terminus is an important determinant of ligand binding affinity as well.36 The ligand specificity that each receptor shows may be a result of differences in the extracellular loops that form lids on the binding cavities or differences in amino acids within the binding cavity. Within the cavity, agonists are thought to bind toward the bottom of the cavity via interactions with a conserved Asp from TM3 and a His from TM6. Molecular modeling calculations show that the phenolic OH of the Tyr1 opioid peptide, or the ring A OH of nonpeptide opioids, forms a hydrogen bond with the conserved His on TM6. The Tyr1-charged nitrogen, or the N+ of the nonpeptide agonist, forms an ionic bond with the conserved Asp of TM3. Antagonist ligands are thought to bind deeper in the binding pocket but retain the ionic bond with the Asp of TM3. The bulky substituent on the charged nitrogen of antagonists is believed to insert itself between TM3 and TM6, preventing the shifts required for activation. Thus, antagonists prevent the necessary movement of TM3 and TM6 resulting in functional antagonism.33,35

THE ^-RECEPTOR

Mu receptors are found primarily in the brainstem and medial thalamus.34 Endogenous peptides for the ^-receptor include endomorphin-1, endomorphin-2, and ^-endorphin

Opioid Receptor Binding Sites

Figure 24.3 • Structure of opioid receptors. (Left) Serpentine model of the opioid receptor. Each transmembrane helix is labeled with a roman number. The white empty circles represent nonconserved amino acids among the MOP, DOP, KOP, and NOP receptors. White circles with a letter represent identical amino acids among all four opioid receptors. Violet circles represent further identity between the MOP-R, DOP-R, and KOP-R. Green circles highlight the highly conserved fingerprint residues of family A receptors, Asn I:18 in TM1, AspII:10 in TM2, CysIII:01 in TM3, TrpIV:10 in TM4, ProV:16 in TM5, ProVI:15 in TM6, and ProVII:17 TM7. Yellow circles depict the two conserved cystines in EL loops 1 and 2, likely forming a disulfide bridge. (IL, intracellular loop, and EL, extracellular loop.) (Right) Proposed arrangement of the seven transmembrane helices of opioid receptors as viewed from the top (extracellular side). The seven transmembrane helices are arranged sequentially in a counterclockwise manner. Each transmembrane helix is labeled with a roman number. (Reprinted with permission from the Annual Review of Biochemistry, Volume 73 © 2004 by Annual Reviews.)

Figure 24.3 • Structure of opioid receptors. (Left) Serpentine model of the opioid receptor. Each transmembrane helix is labeled with a roman number. The white empty circles represent nonconserved amino acids among the MOP, DOP, KOP, and NOP receptors. White circles with a letter represent identical amino acids among all four opioid receptors. Violet circles represent further identity between the MOP-R, DOP-R, and KOP-R. Green circles highlight the highly conserved fingerprint residues of family A receptors, Asn I:18 in TM1, AspII:10 in TM2, CysIII:01 in TM3, TrpIV:10 in TM4, ProV:16 in TM5, ProVI:15 in TM6, and ProVII:17 TM7. Yellow circles depict the two conserved cystines in EL loops 1 and 2, likely forming a disulfide bridge. (IL, intracellular loop, and EL, extracellular loop.) (Right) Proposed arrangement of the seven transmembrane helices of opioid receptors as viewed from the top (extracellular side). The seven transmembrane helices are arranged sequentially in a counterclockwise manner. Each transmembrane helix is labeled with a roman number. (Reprinted with permission from the Annual Review of Biochemistry, Volume 73 © 2004 by Annual Reviews.)

(Fig. 24.2). Exogenous agonists for the /-receptor include drugs from the five structural classes discussed later in this chapter (4,5-epoxymorphinan, morphinan, benzomorphan, 4-phenyl/4-anilido piperidines, and the diphenylheptanes) and exogenous peptides such as dermorphin isolated from the skin of South American frogs. Recently, human neuroblastoma cells have been shown to be capable of synthesizing morphine via biosynthesis from radiolabeled tyramine. The synthetic route involves at least 19 steps and is similar, but not exact, to the synthetic route used by the poppy plant.37 The exact role of endogenous morphine is unknown at this time. In general, agonists at the /-receptor produce analgesia, respiratory depression, decreased gastrointestinal (GI) motility, euphoria, feeding, and the release of hormones. Agonists are also responsible for the addictive effects of the opioid analgesics. Most clinically used opioid drugs bind to the /-opioid receptor.

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