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PubMed1991

Prediction of gas chromatographic relative retention times of stimulants and narcotics.

The ADAPT software system was used to create models for the prediction of gas chromatographic relative retention times (RRTs) of stimulants and narcotics that are analyzed in doping control of athletes. The two main methods that were followed for building the models were the quantitative structure-retention relationship (QSRR) and multiple linear regression analysis. The main proposed model for the entire data set had a multiple correlation coefficient R = 0.991 and standard error s = 0.046 or approximately 4.5%. Because of the relatively high standard error of the main model, a second model was built on a subset of compounds with R = 0.982 and s = 0.027 or approximately 2.5%.

Central Nervous System Stimulants↗
PubMed1981

Structure-activity studies on narcotic antagonists. 2. N-substituted ethyl 3-(m- or p-hydroxyphenyl) nipecotates.

A number of N-substituted ethyl 3-(n- or p-hydroxyphenyl)nipecotates were synthesized to evaluate the role of a m- or p-hydroxy substituted beta-phenethylamine moiety in narcotic antagonist action. Ethyl m- or p-methoxy-phenylcyanoacetate was alkylated with 1-bromo-3-chloropropane. The resultant chloronitriles were hydrogenated (Raney Ni) to amines and cyclized to yield the N-substituted ethyl 3-(m- or p-methoxyphenyl)nipecotates. These were N-benzylated, O-demethylated using BBr3, N-debenzylated, and then N-alkylated. The following N-substituted derivatives were prepared: methyl, allyl, cyclopropylmethyl, and n-propyl. No significant morphine-like analgesic activity was found in mice by the tail-flick method. The acetic writhing assay showed several compounds to possess analgesic activity. N-n-Propyl and N-(cyclopropylmethyl) m-hydroxy derivatives were marginally active antagonists by the mouse tail-flick method. Surprisingly, the N-methyl m-hydroxy derivative, 11m, was found to be an antagonist.

Analgesics↗
PubMed1981

Analgesic narcotic antagonists. 5. 7,7-Dimethyldihydrocodeinones and 7,7-dimethyldihydromorphinones.

Treatment of dihydrocodeinone (1a) or the 8 beta-methyl (1b) or 8 beta-ethyl (1c) analogues with formaldehyde-Ca(OH)2 in aqueous dioxane gave the corresponding 7,7-bis(hydroxymethyl)-6 beta-ols 2a-c. Ditosylation of 2, followed by LiEt3BH reduction, gave either the 7,7-dimethyl-6 beta-ol (6a) or 7 alpha-methyl-6 beta, 7 beta-oxetane compounds (5b,c). Compounds 5b and 5c were cleaved to 6b or 6c using LiAlH4-AlCl3. The configuration of the C6-alcohol group of 6a was confirmed by an oxidation-reduction sequence which gave the 7,7-dimethyl-5 alpha-ol 8a. Oxidation of 6 gave the C6-ketones 7a-c, which were converted to N-(cycloalkylmethyl) derivatives 11 and 12 and their corresponding 3-hydroxy compounds 14 and 15. The 3-methoxy-7,7-dimethyl-6-ones 7 were as active as dihydrocodeinone in agonist assays. One compound of this series, N-(cyclopropylmethyl)-7,7-dimethyldihydronorcodeinone (11a), was a potent mixed agonist-narcotic antagonist.

Analgesics, Opioid↗
PubMed1981

Analgesic narcotic antagonists. 6. 7 beta, 8 beta-Methano- and 7 beta, 8 beta-epoxydihydrocodeinone.

Reaction of codeinone (2) with CH2N2 in the presence of Pd(OAc)2 yielded mixtures of starting material and (2) and 7 beta, 8 beta-methanodihydrocodeinone (3). Initial resolution of this mixture was achieved via carbonyl reduction followed by chromatography to give pure 7 beta, 8 beta-methanodihydrocodeine (4), which was oxidized to 3. Reaction of the mixture containing 2 and 3 with mercaptoethanol and NaOH [2 leads to 8 beta-[(hydroxyethyl)thio]dihydrocodeinone (5)] allowed selective crystallization of 3. The beta configuration of the cyclopropane ring in 3 was established by cleavage with aqueous HCl to give the 8 beta-(chloromethyl) compound 6, followed by carbonyl reduction and dehalogenation to 8 beta-methyldihydrocodeine (8). Reaction of the N-(cycloalkylmethyl) derivatives (13 and 18) of 2 with CH2N2/Pd(OA)2 gave potential mixed agonist-antagonists and 14 and 19, which were purified by reduction-oxidation (14) or mercaptoethanol-base treatment (19). Compound 2, on oxidation with alkaline peroxide, gave the previously reported 7 beta, 8 beta-epoxydihydrocodeinone (22) as the hemimethanol ketal (21). Compound 3 was about ninefold more potent an agonist than dihydrocodeine, and the N-(cyclopropylmethyl)-7 beta, 8 beta-methano compound 19 had moderately potent mixed agonist-narcotic antagonist properties.

Analgesics, Opioid↗
PubMed1981

Analgesic narcotic antagonists. 8. 7 alpha-Alkyl-4,5 alpha-epoxymorphinan-6-ones.

The preparation of a series of 7 alpha-alkylated dihydrocodeinones is described. N-(Cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 7 alpha-methyl (a series) or 7 alpha, 8 beta-dimethyl (b series) substituted dihydronorcodeinones (7) were prepared from the appropriately substituted N-(cycloalkylmethyl)-4-hydroxymorphinan-6-ones (5) by dibromination, 4,5-epoxy ring closure, and catalytic debromination. Treatment of 7 with BBr3 gave low yields of the corresponding 3-phenols 8. Alternatively, reaction of dihydrocodeinone (10) with dimethylformamide dimethyl acetal gave the 7-[(dimethylamino)methylene] adduct 11, which was hydrogenated to 7 alpha-methyl- (12) or 7 alpha-(hydroxymethyl)dihydrocodeinone (13). Treatment of 11 with lithium reagents, followed by hydrogenation, gave a mixture of 7 alpha-alkyl (15c-f) compounds and the corresponding 4,5-epoxy-cleaved products 16. Reaction of 11 with alpha-ethoxyvinyllithium gave intermediate 17, which on hydrolysis and hydrogenation yielded the 6,7-furyl (18) or pyrroyl (19) derivative. N-(Cycloalkylmethyl)-14-hydroxydihydronorcodeinones 23P,B reacted with dimethylformamide dimethyl acetal to give 25P,B, which were hydrogenated to the 7 alpha-methyl compounds 26P,B and O-demethylated to give 27P,B. The 7 alpha-methyl-N-methyl compounds were about equipotent with dihydrocodeinone. Derivatives with larger alkyl groups were less potent. Corresponding N-(cycloalkylmethyl) compounds did not show strong mixed agonist-narcotic antagonist activity.

Analgesics↗
PubMed1981

Analgesic narcotic antagonists. 9. 6-Methylene-8 beta-alkyl-N-(cycloalkylmethyl)-3-hydroxy- or -methoxymorphinans.

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.

Analgesics↗
PubMed1980

Analgesic narcotic antagonists. 4. 7-Methyl-N-(cycloalkylmethyl)-3-hydroxymorphinan-6-ones and -isomorphinan-6-ones.

3,6-Dimethoxy-7 beta, 17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinan (2) was converted to the 4-deoxy compound 4 and hydrolyzed to a mixture of the B/C-cis (C series) and B/C-trans (T series) isomers of 7,8-didehydromorphinan-6-one, 5. Hydrogenation of the separated isomers gave 7-methyl-6-oxo derivatives 6a. 7,8-Dimethyl-(6b) or 7-methyl-8-ethylmorphinan-6-one (6c) was prepared by reaction of 5 with lithium organocuprates. The analgesic N-methyl compounds 6 were converted to 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 10--13. Some of these compounds had mixed profiles of narcotic agonist-antagonist effects. Studies with drug-dependent monkeys indicated that several of these compounds with an analgesic-antagonist ratio of less than 0.4 substitute for morphine.

Analgesics↗
PubMed1978

(2-exo-3-endo)-2-Aryltropane-3-carboxylic esters, a new class of narcotic antagonists.

Tropanes 4 bearing an exo aromatic group on carbon-2, an endo-carbomethoxy group on carbon-3, and either a methyl group or a hydrogen on the nitrogen were found to be narcotic antagonists which were devoid of demonstrable analgesic activity. The activity resided in the 1S enantiomer. Compound 4 (R = m-hydroxyphenyl) showed an AD50 of 0.37 mg/kg sc and 1.8 mg/kg po (rats) as an antagonist in the Harris-Pierson modification of the D'Amour-Smith test. The tropane esters for this study were prepared by a Grignard reaction which gave essentially complete 1,4-addition in the absence of copper salts. Nearly equal quantities of esters epimeric at carbon-3 were formed.

Acetylcholine↗
PubMed1978

2,6-Methano-3-benzazocine-11-ropanols. Lack of antagonism between optical antipodes and observation of potent narcotic antagonism by two n-methyl derivatives.

Resolution of a 2,6-methano-3-benzazocine-11-propanol analogue of buprenorphine showed that the biological activity resides in the levo antipode. An attempt to enhance agonist activity by preparation of N-methyl derivatives resulted in two compounds three and five times as potent as nalorphine as antagonists of phenazocine. These compounds are the most potent N-methyl narcotic antagonists reported to date.

Animals↗
PubMed1977

Narcotic antagonists. Synthesis and evaluation of some subsituted 1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines.

A seres of (+/-)-N-substituted 6-ethyl-or -methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines has been prepared from 6 hydroxytropinone. The N-cyclopropylmethyl compounds 10a and 10b were found to be strong narcotic antagonists approximately equivalent to nalorphine. Only slight analgetic activity was found in any of these compounds including the two N-methyl analogues.

Analgesics↗
PubMed1977

5-allyl-9-oxobenzomorphans. 3. Potent narcotic antagonists and analgesics-antagonists in the series of substituted 2',9beta-dihydroxy-6,7-benzomorphans.

5-Allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan methiodide (1) has been converted in a selective two-step process to the corresponding 9beta-hydroxy intermediates 4 and 6, which in turn were transformed via modified von Braun demethylation-acylation to the amides 11 and 21, respectively. These were reduced and demethylated to give a series of 5-allyl-2',9beta-dihydroxy-2-substituted 6,7-benzomorphans 13 and 23, some of which have been found to be highly potent narcotic antagonists and/or analgesics. The resolution of the most interesting compounds (23a and 23b) and pharmacological properties of the optical isomers are also described. Reduction of the double bond in 13 and 23 to give 14 and 24, with one exception, did not appreciably alter pharmacological profiles, while cyclization to the tetrahydrofuranobenzomorphans 25 substantially reduced the level of activities.

Analgesics, Opioid↗
PubMed1982

Narcotic antagonistic potency of bivalent ligands which contain beta-naltrexamine. Evidence for bridging between proximal recognition sites.

Two-bivalent ligands (P-X-P) containing the beta-naltrexamine pharmacophore (P) and a connecting oligoethylene glycol spanner (X) were synthesized and evaluated for narcotic antagonistic activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD). The bivalent ligand 2 whose spanner contains three ethylene units possessed 10-fold greater antagonistic potency than its monovalent analogue (4) in antagonizing the effects of ethylketazocine (EK) on the GPI, while no differential antagonism of morphine was observed among the compounds. In the MVD, 2 was not substantially more potent than 4 as an antagonist against [D-Ala2,D-Leu5]enkephalin (DADLE). The bivalent ligand 3, whose spanner contains six ethylene units, exhibited 15 times greater potency in antagonizing the agonist effects of DADLE on the MVD than its monovalent ligand 4. No marked increase in the ability of 3 to antagonize the effects of morphine or EK on the GPI was observed. The data indicate that mu, kappa, and delta opioid receptors exhibit different selectivity toward bivalent ligands whose spanner lengths differ. The enhanced potency associated with different receptor interactions is consistent with simultaneous occupation of proximal recognition sites. Whether such proximal recognition sites are identical or different remains to be clarified. The distance between proximal sites appears to depend on the opioid receptor subtype involved.

Animals↗
PubMed2005

Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivars.

In the present study morphinan, tetrahydrobenzylisoquinoline, benzo[c]phenanthridine, and phthalideisoquinoline alkaloids were determined qualitatively and quantitatively by HPLC and LC-MS analysis in tissues of the Tasmanian Papaver somniferum L. elite cultivar C048-6-14-64. The data were compared with the results from the low-morphine cultivar "Marianne". In the elite cultivar, 91.2% of the latex alkaloids consist of the three pharmaceutically most valuable alkaloids: morphine, codeine, and thebaine. In the root system, the major alkaloids are sanguinarine/10-hydroxysanguinarine and dihydrosanguinarine/10-hydroxydihydrosanguinarine. In the stems and leaves of C048-6-14-64, the same alkaloids were measured as in the latex. In the stems, a gradient in relative total alkaloid content from the top downward toward the roots was observed. The concentration of morphine was decreasing toward the roots, whereas an increasing gradient from the upper to the lower stem parts was detected for codeine. The relative total alkaloid concentration in leaves remained constant; no gradient was observed. The cultivar "Marianne" displayed a shifted pattern of alkaloid accumulation and reduced levels of total alkaloid. In the condiment cultivar, 80.5% of the alkaloids of the latex consisted of the two phthalideisoquinoline alkaloids narcotoline and noscapine. Only 18.8% of the relative total alkaloid content were morphinan alkaloids. In contrast to the narcotic cultivar, in which the benzo[c]phenanthridines in roots dominated over the morphinan and tetrahydrobenzylisoquinoline alkaloids, the concentration of benzo[c]phenanthridines in "Marianne" was similar to that of morphinan and tetrahydrobenzylisoquinoline alkaloids. These data suggest a differential alkaloid regulation in each cultivar of P. somniferum.

Alkaloids↗
PubMed1997

Effect of narcotic agents and of bleeding on systemic and renal haemodynamics in healthy and CCl4-treated cirrhotic rats.

1. The haemodynamic effects of different narcotic agents have been tested in healthy rats and in rats with cirrhosis. 2. Pentobarbital suppresses the sympathetic nervous system. Susceptibility to ketamine is unpredictable, leading to both insufficient pain relief and narcosis related mortality. The combination diazepam-fluanisone induces profound hypotension. After insertion of catheters, awake, freely moving rats are stable and not distressed. This allows repeated measurements after manipulation. Moreover, procedure-related mortality is low and rats have a better stress response. 3. In the awake animal, arterial pressure is 126 +/- 10 for healthy animals, and 111 +/- 16 and 102 +/- 10 mmHg for cirrhotic animals without and with ascites, respectively (P = 0.018). The respective values for portal pressure are 6.9 +/- 1.4, 11.6 +/- 2.5 and 16.2 +/- 2.9 mmHg (P = 0.0001). After a bleeding, arterial pressure is better preserved than portal pressure in the three groups (P < 0.0001). Plasma volume in cirrhotic rats exceeds that of healthy rats. Plasma renin activity, aldosterone and catecholamines do not differ between the groups studied. In cirrhotic rats with and without ascites, glomerular filtration rate tends to be higher (P = 0.12), renal plasma flow is elevated (P = 0.001) and filtration fraction is lower (P = 0.002) than in healthy rats. 4. In conclusion, haemodynamic experiments in the cirrhotic rat should be performed in the awake rat. Arterial hypotension, impaired filtration fraction, enlarged plasma volume and portal hypertension are present in cirrhosis before the development of ascites. This can as well be explained by splanchnic pooling of blood, as by peripheral vasodilatation. The decrease in portal pressure with preserved arterial pressure after a bleeding protects cirrhotic rats from ongoing variceal bleeding.

Animals↗
PubMedDate not supplied

The sacred journey in dynastic Egypt: shamanistic trance in the context of the narcotic water lily and the mandrake.

Contemporary reference to the role of water lilies and mandrakes (Nymphaea and Mandragora, respectively) in ancient Egyptian healing, and subsequent research on the iconography of the water lily in Mayan shamanistic ritual, suggest the possible importance of these plants as adjuncts to shamanistic healing in dynastic Egypt. Although the usual interpretation of the water lily and the mandrake has been that of a part of ritual mourning, the present article revises this notion. Based on an extensive review of these two powerful narcotic (i.e., hypnotic) plants in iconography and ritual, it is argued that the dynastic Egyptians had developed a form of shamanistic trance induced by these two plants and used it in medicine as well as healing rituals. Analysis of the ritual and sacred iconography of dynastic Egypt, as seen on stelae, in magical papyri, and on vessels, indicates that these people possessed a profound knowledge of plant lore and altered states of consciousness. The abundant data indicate that the shamanistic priest, who was highly placed in the stratified society, guided the souls of the living and dead, provided for the transmutation of souls into other bodies and the personification of plants as possessed by human spirits, as well as performing other shamanistic activities.

Egypt, Ancient↗
PubMed2002

Non-linear modeling of bioconcentration using partition coefficients for narcotic chemicals.

Bioconcentration factors (BCFs) have traditionally been used to describe the tendency of chemicals to concentrate in aquatic organisms. A reexamination of the log-log QSAR between the BCF and Kow for non-congener narcotic chemicals is presented on the basis of recommended data for fish. The model is extended to give a simple correlation between BCF and the toxicity of highly, moderately and weakly hydrophilic chemicals. For the first time, in this study an equation for calculating BCF was applied in a QSAR model for predicting the acute toxicity of chemicals to aquatic organisms.

Animals↗
PubMed2001

Infectious diseases and public health: risk-taking behavior during participation in the Swiss program for a medical prescription of narcotics (PROVE).

The medically controlled prescription of narcotics program (PROVE) followed a uniform protocol from January 1, 1994 until December 31, 1996. The program included 800 slots for heroin prescription, 200 slots for intravenous methadone prescription, and 200 slots for intraveneous morphine. Admission criteria were age 20 and above, minimum 2-year duration of daily heroin consumption, failure in at least two previous treatments, and documented social and/or health deficits. There was a very high seroprevalence of hepatitis B (73%) and hepatitis C (82%) among the 1035 entrants. The rate of HIV (15%) was also high compared with prevalence of infection in other therapy programs (methadone program, inpatient therapy). The prevalence of HIV and hepatitis B/C increased with the duration of drug dependence and cocaine use. During treatment, use of street heroin and cocaine could be reduced substantially. After 18 months of continued participation in the program, 74% of patients reported no illegal heroin consumption, and the rate of cocaine abstinence increased from 15% at entry to 41%. Significant declines in visits to the drug scene, illegal income, and needle sharing were also observed. The high prevalence of HIV and hepatitis B and C confirm that a group of drug dependence with severe medical problems was reached in accordance with the admission criteria for the studies. During treatment, a significant reduction in risk-taking behavior was observed in a target population of heroin-dependent persons who failed in previous treatments.

Adult↗