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Etorphine (Immobilon® or M99) is a synthetic cousin of morphine and 1000 - 80,000 times more powerful. It was invented in 1963 by a research group at McFarlan-Smith and Co. in Edinburgh, led by Professor Kenneth Bentley. It can be produced from thebaine. It is most often used to immobilize elephants and other large mammals. Etorphine is only available legally for veterinary use and is strictly governed by law. Its chemical name is 6,14-endoetheno–7a(1-(R)-hydroxy-1-methylbutyl)-tetrahydro-nororipavine hydrochloride; its CAS number is 14521-96-1. more...

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Diprenorphine (M5050) is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used (1.3 times) to reverse its effects.

Large Animal Immobilon is a combination of etorphine plus acepromazine maleate. An etorphine antidote Large Animal Revivon contains mainly diprenorphine for animals and a human-specific naloxone-based antidote, which should be prepared prior to the etorphine.


Etorphine is an agonist at mu, delta, and kappa opioid receptors. It also has a weak affinity for the ORL1 nociceptin/orphanin FQ receptor.


  • Bentley KW, Hardy DG. Proc Chem Soc 1963;220.; J.Amer.Chem.Soc., 1967, 89, 3281-3292


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Untangling ligand induced activation and desensitization of G-protein-coupled receptors
From Biophysical Journal, 1/1/03 by Woolf, Peter J

ABSTRACT Long-term treatment with a drug to a G-protein-coupled receptor (GPCR) often leads to receptor-mediated desensitization, limiting the therapeutic lifetime of the drug. To better understand how this therapeutic window might be controlled, we created a mechanistic Monte Carlo model of the early steps in GPCR signaling and desensitization. Using this model we found that the rates of G-protein activation and receptor phosphorylation can be partially decoupled by varying the drug-receptor dissociation rate constant, k^sub off^, and the drug's efficacy, alpha. The maximum ratio of G-protein activation to receptor phosphorylation (GARP) was found for drugs with an intermediate k^sub off^ value and small alpha-value. Changes to the cellular environment, such as changes in the diffusivity of membrane molecules and the G-protein inactivation rate constant, affected the GARP value of a drug but did not change the characteristic shape of the GARP curve. These model results are examined in light of experimental data for a number of GPCRs and are found to be in good agreement, lending support to the idea that the desensitization properties of a drug might be tailored to suit a specific application.

Abbreviations used: GPCR, G-protein-coupled receptor; GARP, G-- proteins activated per receptor phosphorylated; MC, Monte Carlo; RGS, regulators of G-protein signaling; RK, receptor kinase.


As a general rule, ligands cause both receptor-mediated signaling and signal desensitization. In the case of G-protein-- coupled receptors (GPCRs), a ligand signals by activating a receptor, which in turn activates a second messenger (G-protein) inside the cell. By holding the receptor in the active state, the ligand also targets the receptor for phosphorylation-a key first step in the desensitization pathway.

In this work we use Monte Carlo simulations of ligand-- induced GPCR signaling and desensitization to learn how these two processes are related and suggest new directions for drug design. Historically drug development has focused primarily on finding drugs that cause a response in the short term, viewing longer-term, drug-induced desensitization as a side effect: However, receptor activation and desensitization are intimately related processes that must both be considered when developing a useful drug. For example, the highly potent (mu)-opioid receptor agonist etorphine is not a medically useful drug because it can only be used a few times before the body becomes desensitized to the drug (Yu et al., 1997). By better understanding how drug properties affect signaling and desensitization, we hope to guide drug development efforts toward new drugs with fewer side effects and a greater range of therapeutic applications.

In a classical view of drug action, receptor signaling and desensitization are simply related; however, experimental data in a variety of systems indicate that the relationship is more complex. According to the classical view, any changes to a ligand that increase its ability to signal would also increase the amount of receptor phosphorylation caused by the ligand. In contrast, experimental measurements of activation and desensitization for the three different receptor systems shown in Fig. 1 indicate that this simple relationship does not hold for a number of well-studied cases. Similarly, ligand-induced activation and desensitization are not simply related in the dopamine D^sub 1^ (Balmforth et al., 1990; Barton and Sibley, 1990) and N-formyl peptide receptor systems (Riccobene et al., 1999), although in these systems the deviation is less severe. Therefore, in many receptor systems, ligand-induced signaling is a poor predictor of the ligand's desensitization ability.

If receptor signaling is not the primary determinant of ligand-induced desensitization, then what is? For a given signaling pathway in a particular cell type, the ability to differentially regulate activation and desensitization must rest with the ligand itself. Here we test the hypothesis that the ligand's binding kinetics and ability to activate a receptor conspire to differentially regulate desensitization and activation. This connection suggests a relatively simple approach to decoupling desensitization and activation via changes in ligand-specific properties.


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Peter J. Woolf and Jennifer J. Linderman

Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109

Submitted May 22, 2002, and accepted for publication August 13, 2002.

Address reprint requests to Jennifer J. Linderman, University of Michigan, 3074 Herbert H. Dow Building, 2300 Hayward, Ann Arbor, MI 48109. Tel.: 734-763-0679; Fax: 734-763-0459; E-mail:

Peter J. Woolf's present address is Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139.

Copyright Biophysical Society Jan 2003
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