MDAN-21

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Structural formula
Structural formula of MDAN-21
General
Surname MDAN-21
other names

7 '- {2 - [(6- {2 - [({(5a, 6a) -4,5-epoxy-3,14-dihydroxy-17-methylmorphin-6-yl} -aminocarbonyl) methoxy] acetylamino} - heptylaminocarbonyl) methoxy] acetylamino} naltrindole ( IUPAC )

Molecular formula C 58 H 71 N 7 O 12
External identifiers / databases
CAS number 873573-64-9
PubChem 101880778
ChemSpider 9847248
Wikidata Q26703469
properties
Molar mass 1058.22 g mol −1
safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

DaN.m-21 is an opioid with two pharmacophores and analgesic properties.

properties

The structure of MDAN-21 was developed in connection with investigations into the biochemical mechanisms of tolerance and addiction development with chronic administration of opioids. MDAN-21 and similar substances have hitherto been used in experimental pharmacology to investigate such biochemical mechanisms.

Mdan-21 contains the chemical structures of two different drug molecules: one, from naltrindole derived structure itself changing the response side effect profile of the other, the oxymorphone derivative Oxymorphamin structure. Oxymorphamine is the actually effective structural element of MDAN-21.

structure

Mdan-21 is a hetero-bivalent opioid receptor - ligand , which consists of a μ agonist (α-Oxymorphamin) and a δ-antagonist (7'-Aminonaltrindol). Both pharmacophores are connected to one another via a flexible spacer. The length of the spacer has a decisive influence on the effect and the side effects . As an analgesic, MDAN-21 is up to 50 times more potent than morphine , can effectively suppress opioid withdrawal syndrome in monkeys with 133 times the effectiveness , but does not lead to self-administration and, in the case of chronic administration, does not lead to physical dependence in comparison with morphine. The substance is therefore being investigated for the withdrawal treatment of opioid addiction .

In MDAN-21, a µ-agonist pharmacophore (α-oxymorphamine) derived from oxymorphone was bound to a δ-antagonist pharmacophore (7'-aminonaltrindole) derived from naltrindole via a 21-atom spacer (25.4 Å). The length of this spacer turned out to be optimal in order to suppress the development of tolerance and physical dependence most effectively while maintaining the analgesic effect. In initial tests on mice, MDAN-21 was found to be up to 50 times more potent than morphine and did not lead to self-administration or the development of physical dependence. In later experiments on 3 monkeys, however, an effective analgesic effect could only be demonstrated in one case. MDAN-21 suppressed the withdrawal syndrome effectively and long-term in all monkeys in the dose range of 6–30 µg / kg (subcutaneously) with a rapid onset of action . At a dose of 30 µg / kg subcutaneously, the onset of action was slightly slower than with morphine, the effectiveness was comparable and the duration of action was longer. The morphine equivalent dose was 4 mg / kg subcutaneously (potency factor 133). The substance could therefore be important for the treatment of opioid addiction.

The signaling unit after the administration of selective µ-receptor agonists are obviously not "isolated" µ-receptors, but rather heteromeric protein complexes . The other receptors can have a modulating influence on the signal cascades triggered by activated µ-receptors and thus the entire spectrum of effects and side effects. The simultaneous administration of µ-agonists together with ligands that selectively bind to another of the above-mentioned receptors can therefore influence the spectrum of activity of the µ-agonists.

Furthermore, the formation of heteromers can be influenced by μ-agonists (or generally by agonists). With chronic administration of agonists, such receptor heteromers can lead to changes in the coupling of the receptor to intracellular signal proteins (e.g. G proteins ) compared to acute administration . In this context, κ-opioid and δ-opioid receptors are of particular importance. A number of studies have shown that κ agonists (U-50488, nalfurafin (TRK-820)) can reduce or block the development of tolerance and physical dependence, as well as the psychotropic effects that lead to self-administration , while κ antagonists ( norbinaltorphimin ) , they increase if they are administered shortly before or together with morphine. With the δ-selective ligands, the situation is reversed. Here, the co-application of morphine with δ-antagonists such as NTI, 5'-NTII, TIPP-Ψ or BW373U86 reduces or blocks the development of tolerance and physical dependence without influencing the analgesic effect.

δ-agonists, on the other hand, increase the development of tolerance and physical dependence with chronic morphine administration. The effect of these 2-active ingredient combinations depends on whether directly adjacent binding sites of a µ-κ or µ-δ heteromer are occupied. This can be achieved most effectively by binding the μ-agonist to the second ligand via a spacer of defined length. The µ-δ heteromer is assumed to be a functional unit that is important for the development of dependency. Therefore, divalent ligands consisting of a µ-agonist and a δ-antagonist were investigated in more detail.

Influence of the spacer length on the development of tolerance and dependency

By varying the length of the spacer, the psychotropic effect and the development of tolerance and dependency can be influenced. MDAN-16 (the ligand with the shortest spacer) induces tolerance and physical dependence, comparable to morphine. MDAN-17 and MDAN-18 induce tolerance but not physical dependence, and MDAN-19 through MDAN-21 induce neither tolerance nor physical dependence. MDAN-16 also leads to self-administration, but not MDAN-19 to MDAN-21. From this it can be deduced that these derivatives presumably show little or no abuse potential.

The opioid receptor forms protein complexes from different proteins ( heteromers ). These include B. heteromers (and also oligomers ) of the type µ-δ, µ-κ, µ-sst 2A , µ-NK 1 , µ-CB 1 , µ-A 1 , µ-mGluR 5 , µ-ORL1, µ-α 2A , µ-CCR 5 , µ-5-HT 1A and µ-GRPR. The mechanisms by which the μ-δ heteromer induces tolerance and physical dependence, or how these are blocked by δ antagonists, are not yet known. However, it could be shown in cells that only express µ-receptors that their activation only triggers inhibitory effects, while in cells that express µ- and δ-receptors an excitatory reaction occurs. Switching the μ-receptors from the inhibitory to the excitatory mode (the receptor then couples to excitatory G s proteins instead of inhibitory G i / G o proteins) has already been repeated earlier by Crain and Shen in investigations into the biochemical mechanisms of the Opioid dependence after chronic opioid administration was examined and described (cf. “Excitatory supersensitivity”). In MDAN-21 the δ-antagonist (7'-aminonaltrindole) modulates the action of the μ-agonist (oxymorphamine) apparently by blocking the δ-receptor influencing an allosteric coupling to the μ-receptor, which affects the coupling of the µ-receptor to intracellular signal proteins or proteins with a regulatory effect (e.g. G-proteins, β-arrestins etc.). This ultimately influences intracellular signal cascades that are responsible for the effects / side effects.

history

The foundations that led to the development of such bivalent opioid ligands go back to the early 1990s, when it was recognized that the pre- or co-application of δ- and κ-opioid receptor ligands together with morphine increased its analgesic effect and increased tolerance - and dependency development as well as the psychological effects leading to self-administration can be reduced. Further research led to the realization that the µ-opioid receptor can form heteromers with numerous other receptors.

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ↑ a b c d David J. Daniels, Natalie R. Lenard, Chris L. Etienne, Ping-Yee Law, Sandra C. Roerig, Philip S. Portoghese: Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series . In: Proceedings of the National Academy of Sciences of the United States of America . tape 102 , no. 52 , December 2005, p. 19208-19213 , doi : 10.1073 / pnas.0506627102 .
  3. ↑ a b c d Mario D. Aceto, Louis S. Harris, S. Stevens Negus, Matthew L. Banks, Larry D. Hughes, Eyup Akgün, Philip S. Portoghese: MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta Antagonist Pharmacophores and Its Effects in Rhesus Monkeys . In: International Journal of Medicinal Chemistry . tape 2012 , April 2012, ISSN  2090-2069 , p. 1-6 , doi : 10.1155 / 2012/327257 .
  4. ↑ a b c Natalie R. Lenard, David J. Daniels, Philip S. Portoghese, Sandra C. Roerig: Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores . In: European Journal of Pharmacology . tape 566 , no. 1–3 , July 2007, pp. 75-82 , doi : 10.1016 / j.ejphar.2007.02.040 .
  5. ↑ M. Gomez-Soler et al: On the Role of G-Protein-Coupled Receptors Oligomerization. In: The Open Biology Journal. 4, 2001, p. 47.
  6. ↑ Tsuneyuki Yamamoto, Masuo Ohno, Showa Ueki: A selective κ-opioid agonist, U-50,488H, blocks the development of tolerance to morphine analgesia in rats . In: European Journal of Pharmacology . tape 156 , no. 1 , October 1988, p. 173-176 , doi : 10.1016 / 0014-2999 (88) 90162-8 .
  7. ↑ Pao-Luh Tao, Chyi-Lin Hwang, Chin-Yuan Chen: U-50,488 blocks the development of morphine tolerance and dependence at a very low dose in guinea pigs . In: European Journal of Pharmacology . tape 256 , no. 3 , May 1994, pp. 281-286 , doi : 10.1016 / 0014-2999 (94) 90553-3 .
  8. ↑ Minoru Tsuji, Hiroshi Takeda, Teruhiko Matsumiya, Hiroshi Nagase, Mitsuaki Yamazaki, Minoru Narita, Tsutomu Suzuki: A novel κ-opioid receptor agonist, TRK-820, blocks the development of physical dependence on morphine in mice . In: Life Sciences . tape 66 , no. May 25 , 2000, pp. PL353 – PL358 , doi : 10.1016 / S0024-3205 (00) 80011-9 .
  9. ↑ Tsutomu Suzuki, Minoru Narita, Yuki Takahashi, Miwa Misawa, Hiroshi Nagase: Effects of nor-binaltorphimine on the development of analgesic tolerance to and physical dependence on morphine . In: European Journal of Pharmacology . tape 213 , no. 1 , March 1992, p. 91-97 , doi : 10.1016 / 0014-2999 (92) 90237-X .
  10. ↑ EE Abdelhamid, M. Sultana, PS Portoghese, AE Takemori: Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice . In: Journal of Pharmacology and Experimental Therapeutics . tape 258 , no. 1 , July 1991, p. 299-303 ( aspetjournals.org ).
  11. ^ Y. Miyamoto, PS Portoghese, AE Takemori: Involvement of delta 2 opioid receptors in the development of morphine dependence in mice . In: Journal of Pharmacology and Experimental Therapeutics . tape 264 , no. 3 , March 1993, p. 1141-1145 ( aspetjournals.org ).
  12. ↑ Tsutomu Suzuki, Minoru Tsuji, Tomohisa Mori, Miwa Misawa, Hiroshi Nagase: Effect of naltrindole on the development of physical dependence on morphine in mice: A behavioral and biochemical study . In: Life Sciences . tape 57 , no. 17 , September 1995, p. PL247 – PL252 , doi : 10.1016 / 0024-3205 (95) 02139-A .
  13. ↑ ME Fundytus, PW Schiller, M. Shapiro, G. Weltrowska, TJ Coderre: Attenuation of morphine tolerance and dependence with the highly selective delta-opioid receptor antagonist TIPP [psi] . In: European Journal of Pharmacology . tape 286 , no. 1 , November 1995, pp. 105-108 , PMID 8566146 .
  14. ^ PH Lee, RW McNutt, KJ Chang: A nonpeptidic delta opioid receptor agonist, BW373U86, attenuates the development and expression of morphine abstinence precipitated by naloxone in rat . In: Journal of Pharmacology and Experimental Therapeutics . tape 267 , no. 2 , November 1993, p. 883-887 ( aspetjournals.org ).
  15. ↑ Cynthia Wei-Sheng Lee, Ing-Kang Ho: Pharmacological Profiles of Oligomerized μ-Opioid Receptors . In: Cells . tape 2 , no. 4 , October 2013, p. 689-714 , doi : 10.3390 / cells2040689 .
  16. ↑ Susan R. George, Brian F. O'Dowd, Samuel P. Lee: G-Protein-coupled receptor oligomerization and its potential for drug discovery . In: Nature Reviews Drug Discovery . tape 1 , no. 10 , October 2002, p. 808-820 , doi : 10.1038 / nrd913 .
  17. ^ AC Charles et al .: Coexpression of δ-Opioid-Receptors with µ-Receptors in GH2 Cells Change the Functional Response to µ-Agonists from Inhibitory to Excitatory. In: Mol. Pharmacol. 63, 1, 2003, p. 89.
  18. ^ Stanley M Crain, Ke-Fei Shen: Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions . In: Trends in Pharmacological Sciences . tape 19 , no. 9 , September 1998, pp. 358-365 , doi : 10.1016 / S0165-6147 (98) 01241-3 .