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At least 19 recordsLinked to original sources
PubMed1983

Analgesic narcotic antagonists. 15. Potent narcotic agonist 7 beta-(arylalkyl)-4,5 alpha-epoxymorphinans.

Structure-activity correlations in 7 beta-(arylalkyl)-3-methoxy- or hydroxy-4,5 alpha-epoxymorphinans have been investigated. 6 beta-Hydroxy-7 alpha-hydroxymethyl compounds 7 with 7 beta-substituents CH2CH2R [a, R = H; b, R = CH2CH3; c, R = C6H5; d, R = CH2C6H5; f, R = CH2CH2C6H5; g, R = (CH2)3C6H5; h, R = (CH2)4C6H5] were prepared. Wittig condensations with previously reported 4,5 alpha-epoxy-7 beta-formyl-7 alpha-(hydroxymethyl)-6 beta, 7 alpha-O-isopropylidene-3-methoxy-17-methylmorphinan-6 beta-ol (3), followed by dilute acid removal of the blocking group and then hydrogenation, gave saturated compounds 7. Compounds with a 6 alpha, 7 alpha-oxymethylene ring. 18c,d,f,g, were prepared from 7 beta-formyl derivative 16 and the appropriate Wittig reagent, followed by hydrogenation. Both the 6 beta-hydroxy-7 alpha-hydroxymethyl and 6 alpha, 7 alpha-oxymethylene series containing 7 beta-arylalkyl groups with an alkyl chain length of 2 to 4 ar potent narcotic agonists. The most potent 17-methyl compound, 4,5 alpha-epoxy-7 alpha-(hydroxymethyl)-17-methyl-17 beta-(4-phenylbutyl)morphinan-3,6 beta-diol (8f) was 700 times more potent than morphine in the acetic acid induced mouse writhing assay. 17-Methyl compounds in the c, d, f, g series were converted to 17-cyclopropylmethyl (P series) or 17-cyclobutylmethyl (B series) derivatives. Narcotic antagonistic activity could not be demonstrated for these potent agonist 17-cycloalkylmethyl derivatives. These pharmacological results parallel those previously reported for tertiary alcohol derivatives of the endo-ethenotetrahydrooripavines. Structureal considerations confirm the existence of a lipophilic site extending upward and outward from where the C ring of morphine and congeners bind to opiate receptors.

Analgesics↗
PubMed1975

Narcotic antagonists. 4. Carbon-6 derivatives of N-substituted noroxymorphones as narcotic antagonists.

A series of new narcotic antagonists has been synthesized by modifying the C-6 carbonyl group in naloxone (Ia) and naltrexone (Ib). New functional units were introduced by reaction with various phosphorus and sulfur ylides and alkyllithium reagents. The activity of the new compounds were measured by the hot-plate and tail-clip tests after oral administration to mice. The majority of the new narcotic antagonists exhibited oral potencies considerably superior to the parent compounds, with 6-methylene derivatives IIa and IIb showing the most impressive increases.

Analgesia↗
PubMed1976

On the ability of narcotic antagonists to produce the narcotic cue.

The ability of narcotic antagonists to produce the narcotic cue was investigated in rats trained to discriminate fentanyl (0.04 mg/kg) from solvent. The partial antagonists pentazocine, cyclazocine and nalorphine were found to possess narcotic cuing activity whereas naloxone lacked any such action at doses up to 160 mg/kg. The relationship between the present findings and the ability of these drugs to produce opiate-like subjective effects in humans is discussed. The conclusion was reached that the experimental procedure used may contribute significantly to the preclinical evaluation of drug abuse liability.

Analgesics, Opioid↗
PubMed1976

Narcotic antagonists. Treatment tool for addiction.

Narcotic antagonists have recently gained attention through research aimed at evaluating both biochemical effects and treatment potential for opiate addiction. Narcotic antagonists are a classification of drugs which block the euphoric (and all other) effects of opiates. Naltrexone is the most promising narcotic antagonist based on ability to produce blockade, length of duration, and relative absence of side effects. The narcotic antagonists offer an adjunctive or alternative method of treatment for opiate addicts based on Wikler's biobehavioral theory of conditioned abstinence. Narcotic antagonists are presently being investigated at seven research centers throughout the United States and may be available for clinical use in the future.

History, 20th Century↗
PubMed1975

Narcotic antagonists: a reasonable method of treating narcotic dependency.

Historically, narcotic dependence has been treated primarily by substituting one narcotic drug for another. One alternative chemical treatment for narcotic dependency is through the use of a narcotic antagonist. The present study involves the observed side effects and outcome results of treating 40 male heroin addicts with the narcotic antagonist, cyclazocine, in the context of a comprehensive psychotherapeutic program. It is concluded that the side effects of cyclazocine are minimal, that cyclazocine is not diverted to the streets, and that it is an effective tool in the context of a comprehensive treatment program for narcotic-dependent individuals.

Aftercare↗
PubMed1976

A behavioral paradigm for the evaluation of narcotic antagonists.

We have developed an experimental paradigm for the behavioral evaluation of narcotic antagonists. The study specifically examined the heroin-seeking behavior of hard-core narcotic addicts on a research ward under blocked and unblocked conditions. Each patient served as his own control. A long-term follow-up program in the community, with aftercare services, was utilized to determine the relationship between behavior observed on the research ward and behavior that occurred in the community. While preliminary one-month follow-up data offered some cause for an optimistic view of narcotic antagonist treatment, behavioral data observed on the research ward raised serious doubts about the possibility of extinguishing heroin self-administration with antagonists. The behavioral data were not consistent with laboratory descriptions of extinction. Rather, the data suggested that narcotic antagonist programs should emphasize the development of contingencies for the reinforcement of narcotic antagonist self-administration to ensure an opiate-free state, instead of focusing on an extinction approach.

Adult↗
PubMed1975

Inhibition of ADH release in the rat by narcotic antagonists.

The diuretic action of two new narcotic antagonists, oxilorphan and butorphanol, was studied in rats heterozygous for hereditary hypothalmic diabetes insipidus. Both drugs caused a prompt increase in urine volume and a decrease in urine osmolality with an associated decrease in urinary ADH excretion. The effects appeared to be dose related and of short duration. Tolerance to butorphanol administration was evident on repeated daily injections. The diuretic effect was not associated with alternation in creatinine excretion, but butorphanol resulted in decreased osmolal, sodium and potassium excretion. Butorphanol prevented the expected rise in urine osmolality and ADH excretion due to 31 h of dehydration. Oxilorphan did not interfere with the ability of administered ADH to cause an antidiuresis. The data indicate that these narcotic antagonists cause a diuresis by inhibiting ADH release from the neurohypophysis.

Animals↗
PubMedDate not supplied

Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

Abnormalities, Drug-Induced↗
PubMed1988

Evidence for the delivery of narcotic antagonists to the colon as their glucuronide conjugates.

Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered s.c. nalmefene HCl caused a dose-dependent tail skin temperature increase, whereas nalmefene glucuronide was ineffective. Nalmefene precipitated brain-mediated morphine withdrawal at doses as low as 10 micrograms/kg, whereas nalmefene glucuronide was ineffective at doses as high as 1 mg/kg. After p.o. administration of the drugs, naloxone HCl and nalmefene HCl caused diarrhea, withdrawal behavior and tail skin temperature responses by 15 min. In contrast, after p.o. administration of the glucuronide conjugate of either narcotic antagonist, diarrhea was delayed for 75 to 203 min. This latency probably reflects the required transit time to the lower gastrointestinal tract inasmuch as direct colonic administration of either nalmefene or nalmefene glucuronide caused diarrhea within 5 to 8 min. Additionally, the magnitude of brain-mediated withdrawal was smaller and its time of occurrence was delayed and compared to the diarrhea response after p.o. administration of the conjugated forms of the narcotic antagonists. Our calculations indicate that about 0.2 to 0.5% of the dose of the narcotic antagonist administered orally as the glucuronide was absorbed systemically. These results indicate that p.o. administration of the glucuronide conjugates of naloxone and nalmefene results in delivery of the narcotic antagonists to the colon. As such these conjugates may be useful in the prevention or relief of constipation caused by opiate use, without interfering with the central analgesic effects of the narcotics.

Animals↗
PubMed1975

Quantification of the analgesic activity of narcotic antagonists by a modified hot-plate procedure.

The analgesic activity of morphine and the narcotic antagonists, pentazocine, cyclazocine, levallorphan and nalorphine, was assessed in the rat using two hot plates: one maintained at 49.5 degrees C and the other at the "standard" 54.5 degrees C. The analgesic effects of morphine using the 49.5 degrees C hot plate were of a significantly greater magnitude than its effects using the 54.5 degrees C hot plate for both nontolerant and morphine-tolerant subjects. Dose-related effects were observed with all of the narcotic antagonists tested using the 49.5 degrees C hot plate; only the highest dose of pentazocine exhibited activity using the 54.5 degrees C hot plate. Naloxone (3.0 mg/kg) antagonized the analgesic effects of morphine and all of the narcotic antagonists, but was without activity itself when tested using the 49.5 degrees C hot plate at doses as high as 30 mg/kg. Aspirin was also inactive using the 49.5 degrees C plate, whereas physostigmine increased latencies only at a dose that produced severe motor deficit. A low temperature hot plate is recommended for evaluating the analgesic activity of narcotic antagonists in the rat. This simple procedure provides results which are dose-related, quantifiable, reproducible, of a large magnitude and specific.

Analgesia↗