Fentanyl-derivative

Kolokol-1 (Used by Russians to end 2002 theater hostage situation. Thought to be a fentanyl derivative.)... 

Lofentanil—another extremely potent fentanyl derivative that is 6,000 times stronger than morphine and is very long-acting (i.e., hours), so it is used only for prolonged surgical procedures and treatment of multiple trauma-related injuries. 

The interior volume of the theater, estimated from illustrations, was probably less than three hundred thousand cubic feet, i.e., about 10,000 cubic meters. Based on doses used for anesthesia, a concentration of as little as 2-3 mg per cubic meter of a super-potent Fentanyl derivative might be sufficient for a building that size, if instantaneous incapacitation is not required. This assumes continuous inhalation for about 30 minutes. Thus, if evenly distributed, the total amount of drug required might be in the range of a few dozen grams - almost certainly less than a pound. If the Russian authority pumped in 5x the effective dose (as it claimed), its uneven distribution in the air would likely have caused many deaths. But only one in six died. 

Some articles, for example, include an identical table of effective and lethal doses of high potency Fentanyl derivatives. The estimated safety margins are as high as 30,000. I could find no source for these data. I sent out several inquiries but thus far have received no definitive answers. I also discussed the questions with Harry Salem, who continues to study the toxicology of opioids at Edgewood. He is hopeful that the concomitant use of drugs tailored to suppress the effect of potent opioids on respiration may produce much safer agents. 

Perhaps the most successful modification of the 4-phenylpiperidine derivatives of morphine is the 4-anilino compounds, such as fentanyl (3.15). This dmg is 50-100 times more active than morphine, owing mainly to its excellent transport across the blood-brain barrier and into the CNS as a result of its high lipophilicity. Spectacular activities ( 5000-6000 times that of morphine) have also been achieved by introducing ether or keto substituents (sufentanil), as in the meperidine or ketobemidone series. Fentanyl derivatives are very fast acting and of short duration. They are used in neuroleptanalgesia in surgery, in combination with neuroleptics or major tranquilizers like droperidol. 

Naloxone Narcotic drugs, other opioid derivatives A specific antagonist of opioids 1-2 mg initially by IV, IM, or subcutaneous injection. Larger doses may be needed to reverse the effects of overdose with propoxyphene, codeine, or fentanyl derivatives. Duration of action (2-3 hours) may be significantly shorter than that of the opioid being antagonized. 

Fentanyl and fentanyl derivatives (so-called designer drugs) have a fundamental abuse potential (Buchanan and Brown, 1988)) and induce morphine-type physical dependence. 

Fentanyl derivatives [Sublimaze, others] Hydromorphone [Dilaudid, Hydrostat] Levorphanol [Levo-Dromoran] Meperidine [Demerol]... 

The major physiological effects of fentanyl are euphoria, drowsiness, respiratory depression, decreased gastrointestinal mobility, nausea, and muscular rigidity. People build up a tolerance to fentanyl the more they use it, causing them to need more to obtain the same effects they once received from a smaller dose. The high of fentanyl can last 10-72 hours, depending on the ingestion method, the fentanyl derivative used, and the amount taken. 

This situation became particularly acute with respect to the development of illicit analogs of fentanyl to derive heroin substitutes. Fentanyl is a synthetic opioid, a p-receptor agonist, and is about 100-200 times more potent than morphine as an analgesic. As with other narcotic analgesics, respiratory depression is the most significant acute toxic effect of the fentanyl derivatives. Fentanyl analogs can be 80-1000... 

Gerak LR, France CP (1999) Discriminative stimulus effects of flumazenil in untreated and in diazepam-treated rhesus monkeys. Psychopharmacology 146 252-261 France CP, Gerak LR, Winger GD et al. (1995) Behavioral effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys. J Pharmacol Exp Ther 274 17-28 France CP, Medzihradsky F, Woods JH (1994) Comparison of kappa opioids in rhesus monkeys behavioral effects and binding affinities. J Pharmacol Exp Ther 268 47-58 France CP, Moerschbaecher JM, Woods JH (1991) MK-801 and related compounds in monkeys discriminative stimulus effects and effects on a conditional discrimination. J Pharmacol Exp Ther 257 727-734... 

France CP, Gerak LR, Winger GD, Medzihradsky F, Bagley JR, Brockunier LL, Woods JH (1995) Behavioral effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys. J Pharmacol Exp Ther 274 17-28... 

The spirane ring is formed by treating amides derived from 16 with formamide and reducing the product.(20,56) In the solid state the 4-NPh moiety adopts an equatorial rather than an axial conformation in relation to the piperidine ring,(57) akin to the solid and probable solute state conformation of fentanyl, for which there is X-ray<58) and H-nmr evidence (see 20). The activities of the spiranes 19 also provide evidence that anilido phenyl is a- rather than /3-oriented in active conformations of fentanyl derivatives (21). This aromatic feature is confined to the /3-orientation in the bicyclo analogs 22, neither of... 

Moscow theater - Fentanyl derivatives used against terrorists... 

Illicit fentanyl derivatives are synthesized in clandestine laboratories solely for substance abuse. In the United States, these agents are classified as restricted Schedule I substances. 

Illicit fentanyl derivatives may be nasally insufflated as powder or solubilized and injected intravenously. 

The exact kinetics of illicit fentanyl derivatives is uncertain. Kinetics may vary with each manufactured product batch. Fentanyl derivatives are rapidly absorbed across mucous membranes. Addicts report an onset of action or rush within 90s of administration. Illicit derivatives may be up to 6000 times more potent than morphine. Like their pharmaceutically manufactured counterparts, illicit fentanyl derivatives are likely metabolized by the liver. 

Illicit fentanyl derivatives act as agonists at the opioid receptor. Unsuspecting heroin users typically administer their usual dose of heroin, and receive variable amounts of the more potent fentanyl analog. These agents produce profound central nervous system and respiratory depression through mechanisms common to other opioids. 

The effects of illicit fentanyl derivatives in many animals may be similar to the actions of fentanyl. Swine... 

The toxic effects of illicit fentanyl derivatives include rapid onset respiratory and central nervous system depression. Patients often present comatose and apneic. Other signs and symptoms consistent with opioid intoxication such as bradycardia, hypotension, miosis, and decreased gastrointestinal motility also occur. 

Basic and advanced life support measures should be initiated immediately. Activated charcoal may be utilized to adsorb illicit fentanyl derivatives following ingestion. Naloxone is the specific pharmacologic antagonist for fentanyl derivatives. Naloxone displaces these agents at the opioid receptor and reverses their clinical effects however, higher than customary doses may be needed to successfully overcome the opioid receptor. 

Fentanyl Derivatives, Illicit, Pages 324-325, Amanda Lofton SummaryPlus Full Text + Links PDF (59 K)... 

Rice and co workers prepared a variety of affinity labels on the basis of the structures of eto-nitazine, fentanyl, and oripavine (Fig. 7.39) (198, 461). The etonitazene derivative BIT (196) selectively inactivates /a receptors, whereas the fentanyl derivative FIT (fentanyl isothiocyanate, 197) and the oripavine derivative FAO (fumaramido oripavine, 200) selectively inactivate 6 receptors. The selective alkylation of S receptors by FIT, which is a derivative of the p-selective ligand fentanyl. 

Sufentanyl (R-30,730)(18) was the most potent compound in a novel series of 4-substituted fentanyl derivatives. Sufentanil, which is 4500 times more potent than morphine, has a rapid onset but relatively short duration of action and its margin of safety is reported to be unusually high (LD5Q/ED50>25000).146... 

We have already noted that a fentanyl derivative was used in Russia in 2002 to end the Moscow theatre hostage crisis. In the United States such agents and related opioids were still being researched in the early 1990s, as were agents that could affect a2-adrenergic transmitter/ receptor systems.37 Also, some of the natural agents understood... 

Morphine causes histamine release, which can cause bronchoconstriction and vasodilation, and should be avoided in patients with a history of asthma. Other /i-receptor agonists that do not release histamine, such as the fentanyl derivatives, may be better choices for such patients. 

Substitution of tetrazol-5-one for the thiophene ring in sufentanil results in a decrease in potency ( 25 times that of morphine) and a decrease in the pKa of the resultant compound, alfentanil (Table 24.4). The lower pKa of alfentanil results in a lower percentage of the drug existing in the ionized form at physiological pH. Being more un-ionized, alfentanil penetrates the blood-brain barrier faster than other fentanyl derivatives and has a faster onset and shorter duration of action. Alfentanil is 99% metabolized in the liver and has a half-life of only 1.3 hours. Alfentanil is available as an intravenous dosage form for use in ultrashort anesthetic procedures. 

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