User:Nuklear/Ohmefentanyl
From Wikipedia, the free encyclopedia
Contents |
[edit] Background
Over the past several years the processes of learning and memory and drug addiction have converged. Drug addiction is an aberrant form of learning and memory that exacts enormous tolls on society. Once formed, drug addiction can be a life–long phenomenon and relapse can occur after years (even decades) of abstinence. In this vein, consumption of addictive substances must lead to exceedingly stable changes in neurobiology. Neurobiologists, pharmacologists, and medicinal chemists alike have made steady progress in trying to identify the molecular, cellular and behavioral underpinnings of drug addiction so that it can be better understood. Ohmefentanyl (OMF) is a member of the superpotent club of opioids and consists of eight stereoisomers. Carfentanil is another superpotent fentanyl analog, although its half–life is reported to be relatively short. In addition, etorphine is a thebaine derived semi-synthetic opioid discovered by Bentley & Hardy in the 1960's that belongs to the same family of compounds as buprenorphine. The technology does not yet exist so that superpotent opioids can be safely administered to humans in that their dosage is in the region of 1–5ug, which is incredibly low. As will be discussed in this article, the most potent isomer of OMF (F9204; RTI-1a) has pharmacologic properties that make it an intensely interesting research compound for decoding the underpinnings of drug addiction. Dihydroetorphine has also been studied by the Chinese and was found to possess a similarly low propensity to cause physical dependancy. One must realize that a lowered physical dependency will only become apparent during opioid withdrawal. An opioid with low physical withdrawal can still possess a high degree of psychological dependance. Therefore the propensity for self-administration can still be high.
[edit] Physical Dependency
Nestler & Aghajanian, 1997. Eric Nestler, 2001. Chao, J. and Nestler, E.J. (2004)
[edit] OMF QSAR
Ohmefentanyl (β-hydroxy-3-methylfentanyl) is an immensely powerful analgesic and a member of the 4-anilidopiperidine class of opioids. It is also in the club of superpotent opioids. Other members of this class include carfentanil, oripavine derived etorphine, and the cyclohexanol compounds discovered by Daniel Lednicer.[1]
The mixture of the cis-OMF ~28 x fentanyl, whereas F9204 = 6.3K x morphine in mice (Jin, et al. 1996).[2]
Repeat dosing can result in physical dependence. The potential of compound to induce dependence was preclinically evaluated in different animals. The ability to develop physical dependence to OMF is lower than morphine, similar to fentanyl.
Particularly noteworthy is the strength of F9204 (RTI-1a) and F9202 (RTI-1b). These opioids have a dosage that is perhaps only 1-2% of that needed for fentanyl. The potencies sjpwn in the table are only approximate. Other extremely potent opioids are etorphine and carfentanil used in immoblizing wild animals. However, aside from potency there are other biochemical qualities that make OMF a special opioid worthy of pre-clinical evaluation.
Although these are similarly potent opioid analgesics, it is important to clarify distinctions that can be drawn between psychological and physical dependencies.
In separating out the isomers of ohmefentanyl, the following biochemical properties are obtained:
| Compound | Absolute Configuration | mp°C | [α]25D (MeOH) | ED50 | Mor=1 | WJCED50 | DPI |
|---|---|---|---|---|---|---|---|
| F9204 (RTI-1a) | (+)-cis-(2'S,3R,4S) | 117–119 | +19.79 | .00106 | 13110 | .0984 | 92.8 |
| F9203 (RTI-1c) | (–)-cis-(2'R,3S,4R) | 107–108 | –20.54 | >10 | 9.941 | <1 | |
| F9202 (RTI-1b) | (–)-cis-(2'R,3R,4S) | 135–137 | –31.91 | .0046 | 2990 | .0007 | .15 |
| F9201 (RTI-1d) | (+)-cis-(2'S,3S,4R) | 117–119 | +33.15 | >10 | >60 | >6 | |
| (–)-trans-(βS,3R,4R) | 107–109 | –0.49 | .0097 | 1450 | .0445 | 4.6 | |
| (+)-trans-(βS,3S,4S) | 98–100 | +62.24 | .014 | 985 | .0303 | 2.2 | |
| (–)-trans-(βR,3R,4R) | 98–100 | –58.11 | .014 | 980 | .361 | 5.0 | |
| (+)-trans-(βR,3S,4S) | 107–108 | +0.78 | .0710 | 196 | .383 | 5.1 |
Rats dependent on morphine jump up and down during withdrawl and this can be intensified by administering naloxone. Interestingly F9204 mice did not jump whereas F9202 mice would do. Since this test is suppose to indicate physical dependency, it was concluded that F9204 is not physically addictive (or at least not at the dosage required to maintain analgesia).[3]
The dependency potency index (DPI) was calculated as withdrawal jumping culmulative ED50 ÷ analgesic dose. Higher DPI indicates relatively lower dependent capacity. DPI of F9204 is maximal, over 618-fold higher than that of F9202, another extremely potent analgesic.
Controlled place preference (CPP) is suppose to indicate psychological dependency. F9204 exhibits strong CPP relative to saline as does morphine (Can Gao, et al. 2003).[4] CPP was also demonstrated for F9202 but not to quite the same extent as for F9204 and morphine. All three compounds increased Ser133 phosphorylation of CREB in the hippocampus. Ser133 phosphorylation was approximately equal on day 3, but by day seven F9204 was markedly stronger than for morphine and the effect was also longer lasting than for F9202.
It is hypothesized that psychological opiate dependency may be directly proportional to the intrinsic activity of the mu-opiate agonist.[5] [6]
[edit] Role of Glutamate
With regard to the above paper, a particularly interesting finding is that because of the colocalization that exists between glutamatergic neurons and opioid receptors, ketamine was able to reverse CPP and Ser133 phosphorylation of CREB almost entirely. Although NMDA antagonist activity can reverse opioid tolerance and dependence, according to one document quoted in the Nestler 1997 paper, these properties might actually increase addiction and therefore should not be considered a successful treatment strategy. In further considering the role of NMDA antagonism with respect to opioid tolerance and dependence, various synthetic opioids have been shown to display built-in NMDA antagonist affinity, methadone and ketobemidone are two such examples. Furthermore, the combination of morphine and methadone has recently been indicated because of this. This might be qualitatively reasoned as an opiate "sparing" approach, decreasing the dosage of an opiate that would inordinarily have to be consumed to achieved a desired effect. In this respect, ketamine has been reported to be similar to heroin in terms of effects and like GABAergic compounds can serve to decrease the intensity of opiate withdrawal. Phenylcyclidine is another potent NMDA antagonist, although it is less well known in the above context. However, besides dizocilpine, the m-hydroxy analog of phencyclidine is one of the most potent NMDA antagonists identified and interestingly has opioid antagonist actions! The cyclohexanol compounds first discovered by Lednicer et al. also have a QSAR similar to PCP and the m-hydroxy analogs of these compounds are have antagonist pharmacology.
[edit] Nestler Papers
Physical dependency is suppose to be mediated in the locus coeruleus (LC), which is the same area of the brain from where noradrenergic signaling originates. Acute versus chronic opiate and psychostimulant dosing leads to many interesting changes in signaling cascades.
Dosing on an opiate (e.g. morphine) slows the firing rate and electrical excitability of LC neurons. However, upon withdrawal, LC neurons show a rebound increase in firing rates. The introduction of the α-adrenergic agonist clonidine for the treatment of opioid withdrawal is based on this understanding of the neurochemistry at the level of the LC.
The cAMP pathway is also inhibited after acute opiate dosing. Upon chronic dosing, the cAMP pathway becomes upregulated as a compensatory measure. During withdrawal, cAMP signaling is then dramatically increased and this is associated with mediated some of the negative effects accompanying opioid withdrawal. CREB lies downstream of cAMP and is also affected by opiate administration in a manner similar to cAMP signaling. Since Ser133 phosphorylation of CREB obviously regulates nuclear transcription, it would be interesting to find out more about the transcription factors that are regulated by CREB.
DFosB is thought to accumulate upon repeat administration of an opiate. It is stable and accumulates upon repeat administration, although only a small induction is noted after a single dose. DFosB increases senstivity to an opiate. Mice with high DFosB will work harder to self-administer and will do so at lower dose versus control mice. The fact that DFos hangs around for weeks rather than hours/days has led some to speculate that this could underlie long-term changes in the morphology of cellular targets though to mediate long-term changes responsible for the even life-long suceptibility of addicts to relapse. DFosB is induced by other drugs of abuse such as cocaine, and also non-drug reinforcers like running and sucrose administration.
CREB is more significant in the acute actions of opioids whereas DFosB becomes the dominant influence after chronic exposure.
[edit] References
- ^ [1]USPAT 7,183,436
- ^ [2]Jin WQ, Wang ZX, Chen J, Chen XJ, Chi ZQ. Analgesic activity and selectivity for opioid receptors of enantiomers of ohmefentanyl. Acta Pharmacol Sin. 1996 Sep;17(5):421-4.
- ^ [3]Gui-Wen Guo, You He, Wen-Qiao Jin, Yong Zou, You-Chen Zhu and Zhi-Qiang Chi Comparison of physical dependence of ohmefentanyl stereoisomers in mice. Life Sciences Volume 67, Issue 2, 2 June 2000, Pages 113-120
- ^ [4]Can GAO, Li Wei CHEN, Jie CHEN, Xue Jun XU, Zhi Qiang CHI. Ohmefentanyl stereoisomers induce changes of CREB phosphorylation in hippocampus of mice in conditioned place preference paradigm. Cell Research (2003); 13(1):29-34.
- ^ [5] Zhong-Hua Liu, You He, Wen-Qiao Jin, Xin-Jian Chen, Qing-Xiang Shen and Zhi-Qiang Chi. Effect of chronic treatment of OMF stereoisomers on cyclic AMP formation in Sf9 insect cells expressing human μ-opioid receptors. Life Sci. 2004 Apr 30;74(24):3001-8.
- ^ [6] Effects of ohmefentanyl stereoisomers on phosphorylation of cAMP- response element binding protein in cultured rat hippocampal neurons. Acta Pharmacol Sin. 2003 Dec;24(12):1253-8.
- ^ [7]FENG Ya-Ping, CHEN Li-Wei, ZHOU De-He, CHEN Jie, XU Xue-Jun, CHI Zhi-Qiang (2001) Analysis of binding domain and function of chimeric ¦Ì/¦Ê opioid receptors to ohmefentanyl stereoisomers. Acta Pharmacol Sin. Vol 22 Issue 11
