1.3.	Opioid agonists and antagonists
In this section, a short summary of this broad subject is given. This is already discussed in a review article 51 on opioid agonists, antagonists and receptors.
Since the subtyping of the opioid receptors and the discovery of endogenous opioids, a renewed search for pain medication with acceptable side effect spectra has been initiated. The endogenous opioids present in mammals are built off three precursor molecules, namely pro-opiomelanocorti, proencephalin and prodynorphin. Further opioid peptide families, dermorphin and deltorphin, have been isolated from the skin of amphibians. Among the exogenous opioids we count β-Casomorphines, which are fragments of bovine β-caseins (Table 1).
The discovery of endogenous peptides led to the synthesis of numerous new peptides and peptide analogs with a strong analgesic effect, longer duration and increased receptor specificity.
The presently used opioids in pharmacotherapy generally act on the µ-receptor. However, these substances show not only a high degree of analgesia, but also strong side effects like tachycardia, bradycardia, obstipation and tolerance development. The cause of this is the limited specificity of the opioid ligands for certain receptors. These substances don’t just act on the µ1- but also the µ2- receptors and also have an impact on the endocrine system.
[[Table 1 – overview of the naturally occurring opioid peptides]]

The goal is thus, to find highly specific opioids that only target one receptor subtype, with a narrow side effect spectrum. In the µ-selective substance group, loperamide and codeine can be found, both of which are already used in practice. The newest drugs, which are most often administered following surgical procedures, are fentanyl, sufentanil, alfentanil and tramadol.
Morphine is the original structure for many non-peptide µ-opioids. In the next table (Table 2), a selection of peptide and non-peptide µ-ligands are summarized.
[[Table 2: µ-opioid agonists (AG) and –antagonists (AT)]]
Selective δ-receptor agonists appear to have a more narrow spectrum of side effects in comparison to µ-receptor agonists. As of recently, non-peptide δ-agonists are available. Important representatives are (+)-SNC80 and (+/-)-BW373U86. The non-peptide antagonists are derived from µ-selective compounds. This lead to the δ-selective Naltrindol.
Even though a multitude of δ-receptor specific ligands is known, they are not yet used in practice. Reason for this is a slew of side effects, such as sedation or effects on the gastro-intestinal tract. The δ-selective peptide agonists are mostly derivatives of encephalins, dermorphins and deltorphins. For instance, by switching out the amino acids glycin for D-alanine in Leu-Encephalin of the DADLE connection (Table 3). However, these connections are not very specific, as they can happen at both the δ- and µ-receptors. To lower the affinity for the µ-receptor, sterically hindering voluminous groups (e.g. tert¬-butyl) were introduced. Through cyclization, a further rigidizing effect is achieved. An example of this is the δ-selective opioid t-Hpp-JOM-13.
[[Table 3: δ-Opioid agonists and –antagonists]]
κ-selective opioids are characterized by powerful analgesia, while the µ-specific side effects such as respiratory depression, obstipation and physical dependency seem absent. These substance were seen as the future of powerful analgetics. Even so, in κ-selective opioids, another side effect spectrum such as sedation, dysphoria and diuresis, limiting the therapeutic use of these compounds.
The first non-peptide κ-agonists were the benzomorphans, with ketocyclazocin as the most important representative. A distinct influence on the development of κ-selective opioids was the discovery of the analgetic effects of arylacetamide by Upjohn et al58-59. The structural origin for these structures is U-50488 (Table 4), showing high selectivity and receptor specificity. Modifications in the aryl- and cyclohexane parts of arylacetamide lead to compounds such as U-62066 (spiralodin) and U-69563 (Table 6), which show similar effect profiles. The affinity and selectivity of the κ-receptor is significantly increased in the benzofuran  derivative CI-977 (enadolin). A further interesting group of arylacetamides are the EMD-Derivatives of Gottschlich et al64,65. These derivatives have four stereo-isomeric forms, that show distinct κ-receptor affinity.
Κ-selective antagonists, developed by modification of dynorphin A, have as of yet eluded us. The most well-known κ-antagonist i norbinaltorphimin, where pyrrol serves as a spacer. This compound was shown to be very active and selective. In table 4 the structures of some non-peptide κ-agonists and –antagonists are listed. In the next chapters, the κ-selective bicylcononanones are extensively discussed.