Search PubMed⌕ Search

Biomedical subjects

S Archer

Publications and source records attributed to S Archer.

At least 109 records · Page 6Linked to original sources
PubMed1983

Analogues of hycanthone and lucanthone as antitumor agents.

Hycanthone analogues (5 and 6) containing 7-substituted hydroxyl groups were prepared and evaluated as antitumor agents. These compounds were significantly more active than the corresponding unsubstituted derivatives. The 7-hydroxylated 4-(hydroxymethyl)-9H-xanthen-9-ones, 11 and 12, were also active antitumor agents. However, the 7-hydroxy-9H-xanthen-9-one counterparts of the 7-hydroxylucanthones were totally devoid of antitumor activity. Results obtained thus far are consistent with the hypothesis that 4-hydroxymethyl substituents in the 9H-xanthen-9-one and 9H-thioxanthen-9-one series are required for antitumor activity.

Animals↗
PubMed1983

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 2. Non-glycolates.

The 19 esters in Table I were prepared from (+)-2 alpha-tropanol, (-)-2 beta-tropanol, (+/-)-3-quinuclidinol, and a variety of non-glycolic acids in order to compare their central and peripheral activities with those of the glycolates reported in the previous paper. The results (Table II) showed that esters 6 and 17 were approximately equivalent to one another and to atropine, that 8 was equal in both central and peripheral activity to reference glycolates, that 9 and 19 were less active than 8 but 9 had a substantially reduced central activity, and that 10 and 11 were more active than the methoxy analogue reported earlier.

Animals↗
PubMed1983

14 beta-(2-bromoacetamido)morphine and 14 beta-(2-bromoacetamido)morphinone.

14 beta-(2-Bromoacetamido)morphine (6) and 14 beta-(2-bromoacetamido)morphinone (9) were prepared preferably from the adduct of thebaine and 1-chloro-1-nitrosocyclohexane, which on reduction in methanol solution gave 14-aminocodeinone (2) and the corresponding ketal (3). When tested in a receptor-binding assay, the IC50 values of 6 and 9 were 15 and 10 nM, respectively. If the incubation time during the assay was increased from 15 to 30 min, irreversible binding of both ligands was observed.

Animals↗
PubMed1982

Torsional motion and elasticity of the deoxyribonucleic acid double helix and its nucleosomal complexes.

Torsional thermal oscillations of the DNA double helix within the electron paramagnetic resonance (EPR) time scale (10(-10)-10(-3) s) as indicated by a rigid, intercalating probe are much smaller in the spacer segment between nucleosomes in chromatin than in long, free DNA molecules. Still smaller DNA oscillation is indicated in intact nuclei and yet smaller if the nuclei have been treated with glutaraldehyde. The values of EPR measurements are not affected by the loading density of probe. If the probe were capable of substantial oscillations or movement different from that of the helix, those oscillations would be expected to dominate the spectra when movement of the helix is restrained. We conclude that the correlation time for torsional movement of free DNA inferred from EPR spectra is characteristic of the double helix and that there is no significant independent motion of the probe. The correlation time for the DNA double helix in molecules longer than approximately 500 base pairs is close to 30 ns, corresponding to an elastic constant of 1.5 X 10(-19) ergs cm for deformation by twisting. The motions observed in chromatin are consistent with a model in which spheres of 50-60-A radius are connected by simple elastic rods with the length of spacer DNA and the same elastic constant. The spin-labeled ethidium probe has been characterized in detail by nuclear magnetic resonance, infrared, fluorescence, and visible light spectroscopy. The binding equilibria are consistent with the hypothesis that strongly immobilized probe molecules are preferentially bound to spacer DNA.

Animals↗
PubMed1982

Ring-hydroxylated analogues of lucanthone as antitumor agents.

A series of ring-alkoxylated and ring-hydroxylated analogues of lucanthone was prepared and tested for antitumor activity. The most biologically interesting members of this group were the 7-hydroxylucanthone derivatives, 50 and 51, which gave T/C values in the NCI P-388 antitumor screen of 188 and 265, respectively. The apparent association constants and delta Tm values for a number of analogue-DNA complexes were determined to ascertain whether there was any quantitative correlation with biological activity. The most that can be said is that intercalation may be a necessary but far from sufficient condition for antitumor activity.

Animals↗
PubMed1982

Nitro and amino derivatives of lucanthone as antitumor agents.

A group of nitro and amino derivatives of lucanthone was prepared and tested for antitumor activity. Reaction of 1-chloro-4-methyl-7-nitrothioxanthenone and N,N-diethylethylenediamine gave the 7-amino analogue (11) directly, accompanied by 7-amino-1-chloro-4-methylthioxanthenone. The antitumor activity of 11 was inferior to that of lucanthone and 7-hydroxylucanthone. The most active compound in the series was the nitro compound 1. In the P-388 lymphocytic leukemia screen it showed a T/C = 178 at 200 mg/kg.

Animals↗
PubMed1982

Affinity labeling and purification of the opiate receptor from rat brain.

Affinity labeling of the opiate receptor has been performed on neural membranes from rat brain utilizing[125I]-14-bromoacetamidomorphine, an opiate agonist, and [125I]-14-chloracetylmorphine, an antagonist. With the use of SDS gel electrophoresis it could be shown that the agonist labeled three proteins with molecular weights of 43,000, 35,000 and 23,000, whereas the antagonist only labeled the 23,000 component. The preferential labeling of the 23,000 protein by the antagonist suggests that this component may be a primary recognition site for opiate antagonists. Calcium was stimulatory to the affinity labeling of all three proteins while sodium was inhibitory. With the use of affinity columns prepared by conjugating either ligand to omega-aminohexyl Sepharose, a receptor complex was obtained consisting all three proteins. Stereospecific opiate binding was demonstrable in the complex prepared from either column.

Affinity Labels↗
PubMed1981

Some 14 beta-substituted analogues of N-(cyclopropylmethyl)normorphine.

A series of N-(cyclopropylmethyl)-14 beta-substituted-normorphine analogues was synthesized and tested for opioid agonist and antagonist activity in the guinea pig ileum and mouse vas deferens preparations. The 14 beta-bromo compound proved to be a pure antagonist equal in potency to naloxone in the guinea pig ileum assay. In contrast to N-(cyclopropylmethyl)-14 beta-hydroxynormorphine which was a pure antagonist, the corresponding sulfur analogue was about equal to nalorphine in agonist and antagonist potency.

Animals↗
PubMed1981

Purification of the opiate receptor from rat brain.

The opiate receptor was purified from a Triton-solubilized preparation of rat neural membranes by the use of affinity chromatography. The affinity gel was prepared by coupling 14-beta-bromoacetamidomorphine, a newly synthesized ligand, to omega-aminohexyl-Sepharose. After elution of the nonspecific proteins with 50 mM Tris (pH 7.5), the receptor proteins were eluted with 1 microM levorphanol or etorphine. NaDodSO4/polyacrylamide gel electrophoresis revealed three major proteins associated with the opiate receptor, having molecular weights of 43,000, 35,000, and 23,000. The purified receptor binds 10(-11) mol of dihydromorphine/per mg of protein, with a Kd of 3.8 X 10(-9) M. Other opiates, naloxone, and methionine-enkephalin, inhibit [3H]dihydromorphine binding in a manner similar to that observed with intact and solubilized neural membranes.

Animals↗
PubMed1981

Historical perspective on the chemistry and development of naltrexone.

The first clinically useful narcotic antagonist was nalorphine. This compound was relatively weak, short-acting, and produced a number of side effects, the most prominent of which were psychotomimetic in nature. For these reasons nalorphine did not qualify as a possible modality for the treatment of heroin addiction. Cyclazocine is a totally synthetic narcotic antagonist which is much more potent and longer acting than nalorphine. It was the first compound used by Martin in clinical trials in postaddicts. However, its dysphoric effects necessitated long induction periods and these CNS effects precluded its use in long-acting delivery systems. Naloxone was a "pure" antagonist which did not produce the psychotomimetic effects of either nalorphine or cyclazocine. Although it is a potent antagonist when given parenterally, it is shorter acting than cyclazocine. Replacement of the N-allyl substituent of naloxone with the cyclopropylmethyl radical of cyclazocine led to naltrexone, which is even more potent than either naloxone or cyclazocine and has a longer duration than naloxone. Because of this favorable combination of properties naltrexone proved to be the drug of choice for inclusion in long-acting delivery systems.

Animals↗
PubMed1980

Synthesis and analgesic activity of some 14 beta-substituted analogues of morphine.

Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 beta-mercaptocodeine with lithium aluminum hydride. 14 beta-Bromo- and 14 beta-chlorocodeinone were prepared by the reaction of thebaine with N-bromosuccinimide and N-chlorosuccinimide, respectively. These 14 beta-substituted codeine and codeinones were O-demethylated to the corresponding morphine analogues with boron tribromide. With the exception of 14 beta-nitromorphinone, which was weak in activity, all the other 14 beta-substituted morphine derivatives were approximately equal in potency to normorphine in the guinea pig ileum preparation.

Analgesics↗
PubMed1977

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 1. Glycolates.

The 38 esters in Table I were prepared from the four isomeric 2-tropanols and a variety of racemic glycolic acids and their optical isomers. Anticholinergic activity in mice was measured in the peripheral nervous system (mydriasis) and in the central nervous system (anti-tremorine) and compared with that of atropine, scopolamine, and racemic 2-quinuclidinyl benzilate. The results (Table III) showed that several esters (such as 8, 12, 14, and 21) had significantly greater activity in both the peripheral and central nervous systems than did the reference compounds. Esters of (+)-2alpha-tropanol were more potent than those of either its epimer (-)-2beta-tropanol or its optical isomer(-)-2alpha-tropanol. Esters derived from (-)-glycolic acids were uniformly more potent than those from the (+)-glycolic acids. Esters of (+)-2alpha-notropanol and five of its N-substituted derivatives had markedly decreased activity. Peripheral/central activity ratios and time-activity profiles for five active compounds are discussed and compared with those of the reference compounds.

Animals↗