Narcotic Antagonist Activity Research Articles

Roles of Two Basic Nitrogen Atoms in 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives in Production of Opioid Agonist and Antagonist Activities.

To ascertain roles of the two basic nitrogen atoms in 1-substituted 4-[2,(3-hydroxyphenyl)-1-phenylethyl]-piperazine derivatives (1) in the expression of opioid agonist and antagonist activities, a methine group (CH) was isosterically substituted for nitrogen atom at the 1-position (N-1) in compound 1 to obtain 4-substituted 1-[2-(3-hydroxyphenyl)-1-phenylethyl]piperidine derivatives (2). Their analgesic action and ability to produce physical dependence (jump-producing activity) as the mu-opioid receptor specific in vivo actions, and narcotic antagonist action in mice were compared with those of compound 1. Results of this study showed that, in cases of the racemate and the (S)-(+) enantiomer, opioid agonist activities (analgesic and jump-producing activities) were not greatly affected by the methine-substitution for N-1 in compound 1, but that the narcotic antagonist activity of the (R)-(-) enatiomer was abolished by this substitution. It thus appears that N-1 in compound 1 contributes to the expression of narcotic antagonist activity, whereas the nitrogen atom at the 4-position corresponds to the tyramine moiety necessary for the expression of mu-opioid agonist activity.

Determination of nalbuphine in drug abusers' urine.

Nalbuphine, chemically derived from the oxymorphone, is a potent analgesic with narcotic antagonist activity. Because of the limited availability of methamphetamine, the abuse of nalbuphine as an alternative for methamphetamine began in late 1991 in Korea. In this study, the analysis of nalbuphine by gas chromatography (GC) was investigated. Using solid-phase extraction, we analyzed drug abusers' urine samples in order to quantitate nalbuphine by GC after trimethylsilyl derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), trimethylsilylimidazole (TSIM), and 1% trimethylchlorosilane (TMCS) (100:2:5). Nalbuphine and its two metabolites, nornalbuphine and 6-ketonalbuphine, were identified by gas chromatography-mass spectrometry. The ratio of total (i.e., nonconjugated and glucuronide) nalbuphine to nonconjugated nalbuphine ranged from 1.8 to 3.0 in the five drug abusers' urine. The urinary excretion of nalbuphine showed that 93% of nalbuphine was excreted in 6 h after intraperitoneal administration of 10 mg/kg nalbuphine to five rats. No nalbuphine was detected in the urine specimens of rats from 24 to 48 h.

Synthesis of N-Substituted C-Normorphinans and Their Pharmacological Properties.

Several N-substituted C-normorphinans (VIII and IX) were synthesized and tested for their analgetic and narcotic antagonist activities and physical dependence capacity. Treatment of N-formyl- octahydro-2-pyrindine (IIIc) with polyphosphoric acid readily gave N-formyl-C-normorphinan (IV). The N-nor bases (V and VII) obtained from IV were converted to VIII and IX. The N-methyl derivative (I), which was previously reported to be inactive by Haffner's method, exhibited potent analgetic activity by the hot plate method and the AcOH-induced writhing test. Compounds VIII and IX showed pharmacological properties similar to those of N-substituted morphinans and exhibited agonist (analgetic) and/or narcotic antagonist activities. The C-nor analogue (IXa) of cyclorphan (IIc) exhibited potent analgetic and antagonist activities with no physical dependence capacity in the single-dose suppression tests both in rats and monkeys.

Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity

Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities comparable to pentazocine but showed no significant physical dependence liability. From these results, it is suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and its surrogates, and belong to a new series of compounds having a potent analgesic activity.

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Historical introduction and review of chemistry.

A historical introduction and review of the chemistry of the agonist-antagonist analgesics is presented. This development of strong analgesics with a lowered abuse potential from nalorphine to the clinically useful agonist-antagonists pentazocine, butorphanol, nalbuphine and buprenorphine is discussed in detail. The discovery of the pure antagonist naloxone and naltrexone is described. The possible use of cyclazocine and later naltrexone in treatment of post-dependent narcotic addicts is also described. Finally, structure-activity relationships are summarized relating changes in N-alkylation to the production of narcotic antagonist activity over all of the structural types of opioids.

Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.

2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan (3a) has been synthesized from 5-(m-methoxyphenyl)-2-methyl-9-oxomorphan (4) and resolved into its enantiomers (+)-3a and (-)-3a. The assigned alpha-orientation of the 9-methyl group was derived from studies of induced NMR shifts using Eu(fod)3-d27. Compound (+)-3a has inappreciable agonist (antinociceptive) activity in mice, and (-)-3a shows codeine-like potency in the hot-plate and writhing tests only. The 9-demethyl homologues, (+)-1 and (-)-1, are strong agonists, about as potent as morphine in these tests as well as in the tail-flick assay. The racemic compound 3a and (+)-3a, but not (-)-3a, exhibit low-potency, narcotic-antagonist activity in mice (tail-flick test, vs. morphine). All three, however, precipitate abstinence in nonwithdrawn, morphine-dependent rhesus monkeys. Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none. Instead, (-)-1 precipitates abstinence in nonwithdrawn animals. Studies in rats and isolated organs (guinea pig ileum and mouse vas deferens) and receptor-binding assays confirm the quite different opioid-action profiles of (+)-1 and (-)-1, which thus might interact with different opioid receptors. Catalytic hydrogenation of the methiodide (7) of 5 gave, instead of the expected epimer of 3a, ring-opened compound 8.

Analgesic and other pharmacological activities of an enkephalin analogue, syndyphalin (SD)-25

The pharmacological actions of Tyr-D-Met(O)-Gly-MePheol (syndyphalin (SD)-25) were compared with those of morphine after systematic administration. The analgesic potency of SD-25 was about 4 times that of morphine when administered s.c. to rats. SD-25 did not exhibit any narcotic antagonist activity. Subcutaneous administration of SD-25 produced a dose-dependent suppression of morphine withdrawal signs in morphine-dependent rats, typical morphine-like jumping in the mouse jumping test, and an increase in spontaneous locomotor activity in mice. These activities were 2–5 times those of morphine. In the anaesthetized dog, intravenous administration of SD-25 produced a 100–1000 times stronger increase in the amplitude of contractions of the jejunum than did morphine, a weaker depression in respiration than morphine, and a slight increase in blood pressure. These effects were reversed by naloxone. These results indicate that SD-25 possesses potent central nervous system actions closely similar to those of morphine, but its effect on blood pressure and respiration was weaker than that of morphine.

Effects of N‐substituted analogs of (−)‐α‐acetylmethadol and (−)‐α‐methadol on schedule‐controlled behavior

AbstractThe behavior of the pigeon maintained under a variable‐interval schedule of food presentation was used to compare the activity of four novel N‐substituted acetylmethadol and methadol analogs with that of methadone and (‐)‐α‐acetylmethadol (LAAM). All of the acetylmethadol and methadol analogs had narcotic agonist activity, as defined by the reversibility of their behavioral effects by naloxone. The effect of the N‐substituted analogs on variable‐interval responding was similar to that of methadone and LAAM, but all these compounds had a slower onset of action than methadone and a shorter duration of action than LAAM. None of the N‐substituted analogs showed narcotic antagonist activity when tested against methadone.

Structure‐Activity Relationship of Oxygenated Morphinans. V. Narcotic agonist and antagonist activity in the 14‐hydroxymorphinan series. Preliminary communication

AbstractThe synthesis of several 14‐hydroxymorphinans, using oxymorphone (= 3, 14‐dihydroxy‐4,5‐epoxy‐N‐methylmorphinan‐6‐one, 1) as starting material, is described. The antinociceptive potency of the N‐methyl substituted 14‐hydroxy‐morphinans was determined. Thus, in order of antinociceptive potency, 14‐hydroxy‐4‐methoxy‐N‐methylmorphinan‐6‐one (5) >4,5‐epoxy‐14‐hydroxy‐N‐methyl‐morphinan‐6‐one (3)>4, 14‐dihydroxy‐N‐methylmorphinan‐6‐one (4)>14‐hydroxy‐4‐methoxy‐N‐methylmorphinan (11) ≈4, 14‐dihydroxy‐N‐methylmorphinan (12). The most potent compound in this series, 14‐hydroxy‐4‐methoxy‐N‐methyl‐morphinan‐6‐one (5), was found to have about six times the potency of morphine; it was equipotent with levorphanol.

Behavioral effects of phenylpiperidine narcotic antagonists

The effects of three phenylpiperidines were studied in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-minute schedule of grain presentation. The first one studied was LY-27372 which has narcotic agonist analgesic effects but not antagonist activity. It decreased responding in both components and was not antagonized by naloxone. The two other drugs, LY-88329 and LY-99335, are tri-alkyl-4-phenylpiperidines which have narcotic antagonist activity. They decreased responding at doses of 5 and 40 mg/kg, respectively, when administered alone. When administered in combination with 20 mg/kg of morphine, they antagonized morphine's effects at 0.16 and 0.08 mg/kg respectively. A 10 mg/kg dose of pentobarbital attenuated the behavioral suppressant effects of 40 mg/kg of LY-99335, but not the suppressant effects of 5 mg/kg of LY-88329 or of 10 mg/kg of LY-27372. The data show that LY-99335 has a large separation between the doses which antagonize morphine and those which alone produce behavioral suppression by a proconvulsant effect at higher doses.

Allylprodine analogues as receptor probes. Evidence that phenolic and nonphenolic ligands interact with different subsites on identical opioid receptors.

The m-hydroxy analogues of allylprodine and related structures have been synthesized and tested for narcotic agonist and antagonist activity on the electrically stimulated guinea pig ileum and by the hot-plate procedure in mice. It has been found that m-hydroxyallylprodine (alpha-2) is neither an agonist nor antagonist. Other phenolic congeners similarly have little or no activity. The fact that these results are in dramatic contrast with the structure-activity profile of morphine and closely related opiates has led to the proposal that the interaction of morphine and allylprodine (alpha-1) with the mu opioid receptor differs. This difference is postulated to arise from the recognition of the aromatic groups of morphine and alpha-1 by different aromatic-binding subsites of the receptor. These subsites are suggested to be identical with those which recognize the aromatic rings of the Tyr1 and Phe4 of the enkephalins and endorphins. A receptor model consistent with these results is proposed.

4-aryl-4-aminocyclohexanones and their derivatives, a novel class of analgesics. 3. m-Hydroxyphenyl derivates.

Derivatives of 4-aryl-4-(dimethylamino)cyclohexan-1-ones substituted by m-hydroxy groups were obtained by using as a key reaction the displacement of cyanide from the alpha-aminonitrile of 1,4-cyclohexanedione ketal, with the THP ether of m-hydroxyphenylmagnesium bromide. A number of the products show narcotic antagonist activity. Amino alcohols obtained on reaction of the free ketones with phenethyl Grignard reagents are potent analgetics, though devoid of antagonist activity. Systematic variation of the substituent on nitrogen revealed nonclassical structure-activity relationships; the dimethylamino group gives the most potent antagonist.

Naloxone Use in Newborns

Naloxone hydrochloride (Narcan) is a pure narcotic antagonist that is the drug of choice in the treatment of central nervous system and cardiores-piratory depression due to narcotic agonist drugs. It has virtually no agonist activity and therefore produces no narcotic effect even when administered in greater than recommended doses, in contrast to nalorphine hydrochloride and levallorphan tartrate, which have mixed agonist-antagonist activity. In 1975 the FDA approved a dosage form of naloxone in a concentration of 0.02 mg/ml that was specifically designed for use in newborns whose mothers receive narcotic analgesics during labor and who are born with narcotic-induced respiratory depression; this drug was marketed for general prescription use. Three years after its introduction, the role of naloxone in the management of the depressed newborn merits clarification. In addition, recent information regarding opiate receptors and endogenous opioids raises questions concerning the long-term safety of naloxone in neonates. A review of available published and unpublished data pertaning to naloxone use in the newborn infant by the Committee on Drugs forms the basis for the following commentary and recommendations. EFFICACY The potent narcotic antagonist activity of naloxone is well documented in infants and children as well as in adults. Naloxone has been effectively used postoperatively to reverse respiratory depression in infants and children who received narcotics for analgesia.1,2 Additional cases have been reported in which naloxone was successfully and safely used to treat children who were poisoned with narcotic agonists such as diphenoxylate hydrochloride (Lomotil),3,4 methadone hydrochloride, 57 and propoxyphene hydrochloride (Darvon).8 Most of the controlled clinical trials to study the safety and efficacy of naloxone in treating respiratory depression in the narcotic-exposed newborn have been carried out on full-term, healthy infants whose mothers received morphine or meperidine hydrochloride during labor, but who showed no overt clinical evidence of respiratory or CNS depression at birth.

Buprenorphine

Buprenorphine, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine-like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine's respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine-like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug's dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time.

ChemInform Abstract: 3‐BENZAZOCINE AMIDINIUM NITRONATES. AN UNUSUAL TYPE OF OPIATE ANTAGONIST

AbstractDi‐, Tri‐ und Tetranitronaphthaline (I) reagieren mit dem Amidin (II) in verschiedener Weise unter Bildung der Benzazocinnitronate (III) und/oder (IV).

3-Benzazocine amidinium nitronates. An unusual type of opiate antagonist.

An interesting type of 3-benzazocine ring system which contains amidine functionality has been found to have significant narcotic antagonist activity. The isomeric 2-benzazocine, which incorporates similar structural features, except for the position of the ring nitrogen and adjacent phenyl substituent, is inactive. These 2- and 3-benzazocines can be synthesized in a single step from appropriately structured amidines and naphthalenes, and such syntheses may provide useful routes to new and interesting types of narcotic antagonists.

ChemInform Abstract: STEREOCHEMICAL STUDIES ON MEDICINAL AGENTS. 23. SYNTHESIS AND BIOLOGICAL EVALUATION OF 6‐AMINO DERIVATIVES OF NALOXONE AND NALTREXONE

AbstractAus Naloxon (Ia) und Naltrexon (Ib) erhält man bei reduktiver Aminierung mit Natriumcyanoboranat in Gegenwart von Ammonacetat die stereoisomeren Amine (II) bzw. (III), die in Relation zur Struktur auf pharmakologische Eigenschaften untersucht werden.

Stereochemical studies on medicinal agents. 23. Synthesis and biological evaluation of 6-amino derivatives of naloxone and naltrexone.

Epimeric 6-amino derivatives of naloxone and naltrexone have been synthesized and the configuration at the C-6 chiral center was determined from NMR studies. All of the derivatives possess narcotic antagonist activity in mice, with each of the 6beta epimers having greater potency than the corresponding 6alpha epimers. In vitro binding experiments indicate that the affinities of these epimers parallel thier in vivo potencies. Slight antinociceptic properties were observed with three of the four compounds. The naloxone derivatives 3a and 3b appear to be attractive candidates for investigation as long-acting narcotic antagonists in view of their fourfold greater duration of action relative to the other antagonists (1, 2, 4a, and 4b).

Azabicycloalkanes as analgetics. 3. Structure-activity relations of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative

A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.