Biomedical subjects

K B Lipkowitz

Publications and source records attributed to K B Lipkowitz.

30 records · Page 2Linked to original sources

PubMed1992

Structural characteristics of cyclodextrins in the solid state.

A comparison of alpha-, beta-, and gamma-cyclodextrins in the solid state is made. Monomeric features analyzed include orientations of primary hydroxyl groups and pyran ring pucker. Macromolecular features examined include planarity of the oligomer, tilting of pyran rings, and, deviation from Cn symmetry where n = number of monomers. The mean values and standard deviations of these shape descriptors are given for cyclodextrins with and without guests embedded in their interiors. Molecular mechanics calculations using the MM2, AMBER, and CHARMM force fields show that most solid state cyclodextrins are trapped in high-energy conformations relative to the most stable forms found in this study.

Chemical Phenomena↗

PubMed1992

Muscimol and N,N-dimethylmuscimol: from a GABA agonist to a glycine antagonist.

By using molecular modeling methods, a molecular mechanism was identified which can explain how the incorporation of two methyl groups in place of two hydrogen atoms on the terminal nitrogen atom of muscimol can not only convert this potent agonist at GABAnergic receptors to an inactive molecule at these receptors, but also can convert this new derivative to an antagonist of glycine at glycinergic receptors. This insight into the molecular mechanism operative in the conversion of physiological function provides a basis for understanding how a single molecule may be able to act at both the GABA- and glycine-inhibitory receptors.

Chemical Phenomena↗

PubMed1992

Efficacy of albendazole and mebendazole against Hymenolepis microstoma and Hymenolepis diminuta.

An investigation of the chemotherapeutic effects of 2 anthelmintics, albendazole (ABZ, methyl 5-[propylthio]benzimidazole-2- carbamate) and mebendazole (MBZ, methyl 5-[benzoyl]benzimidazole-2-carbamate), on Hymenolepis microstoma and Hymenolepis diminuta in experimentally infected mice and rats is reported. Single (50 mg/kg) or multiple daily oral doses (50 mg kg-1 day-1 for 3 consecutive days) of MBZ had no effect on H. microstoma; at necropsy, the drug treated mice harbored appreciable numbers of the parasite in the bile duct and biliary passages. ABZ was also inactive when given as a single oral 50 mg/kg dose on day 27 PI. Better results were obtained when ABZ was administered at a dosage of 50 mg kg-1 day-1 for 3 consecutive days; the reduction in worm burden obtained with this treatment regimen was 50%. These results are in marked contrast to those obtained with the same anthelmintics against enteral H. diminuta in rats which succumbed at lower dosages. A review was made of the published reports on the pharmacokinetic behavior of these benzimidazole carbamate anthelmintics and a hypothesis for the inactivity of MBZ against H. microstoma is proposed.

Albendazole↗

PubMed1991

Molecular modeling of the weak glycine antagonist iso-THAO.

When compared to strychnine, a potent glycine antagonist, iso-THAO, a bicyclic 5-isoxazolol zwitterion, has been reported to be a weak glycine antagonist. Since there are so few glycine antagonists, and there is a striking lack of similarity between the structures of these two antagonists, iso-THAO was studied using current molecular modeling techniques and quantum mechanical calculations in order to compare the structural features and charge distributions of iso-THAO with glycine. The results of this study confirm our earlier hypothesis that an antagonist to inhibitory neurotransmitters like glycine and GABA has at least three binding sites to the natural receptor that are very similar to three such binding sites in the transmitter and its agonists, and each antagonist has an additional negative binding site. We speculate that the latter negative binding site can attach to the top of the chloride channel within the receptor complex. The diminished inhibitory activity of iso-THAO is attributed to its poor structural congruence with the three atom attachment sites used by glycine at its natural recognition site.

Azepines↗

PubMed1991

A molecular modeling approach to in vivo efficacy of triclabendazole.

The structural and electronic features of a narrow-spectrum benzimidazole anthelmintic triclabendazole (TCZ, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylthio-benzimidazole) and its 2 main metabolites triclabendazole sulfoxide (TCZ sulfoxide, 6-chloro-5-[2,3-dichlorophenoxyl]-2-methylsulfonyl-benzimidazole) and triclabendazole sulfone (TCZ sulfone, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylsulfonyl-benzimidazole) have been determined using a combination of quantum mechanics, molecular graphics, and molecular modeling techniques. Using conformational analyses and quantum mechanics, 2 important differences were found between TCZ sulfoxide, the purported active species, and the broad-spectrum benzimidazole anthelmintics. The first distinguishing feature is the shape of the molecule; the substituent at the 2 position of TCZ sulfoxide is nonplanar. All other broad-spectrum benzimidazole anthelmintics, regardless of substituent at the 2 position (methyl carbamate or thiazolyl group), are flat. The second distinguishing feature is the net atomic charge on the substituent at the 2 position of TCZ sulfoxide; it is an order of magnitude larger than the net atomic charges on the other anthelmintics. Thus the nonplanar shape of the methysulfinyl group at the 2 position of TCZ sulfoxide is different (as is its net charge), suggesting that this may be the origin of its narrow spectrum of activity.

Animals↗

PubMed1990

Structure-activity relationships of benzothiazole and benzimidazole anthelmintics: a molecular modeling approach to in vivo drug efficacy.

An investigation of the biochemical effects of an anthelmintic, tioxidazole (TIOX, methyl 6-[n-propoxy]benzothiazole-2-carbamate), on Hymenolepis diminuta in experimentally infected rats is reported. The chemotherapeutic actions of TIOX on H. diminuta in vivo were accompanied by marked changes in worm weight and chemical composition. Tapeworms recovered from rats that had received a therapeutically effective dose of TIOX 24 hr earlier were significantly smaller and contained much less glycogen (as a percentage of the wet weight) than worms from untreated controls. In TIOX-treated worms, protein concentrations rose at a rate sufficient to offset the decline in glycogen concentration. Glycogen/protein ratios in TIOX-treated worms were considerably lower than the corresponding control-values. Differences in the absolute amounts of glycogen and protein between control and drug-treated worms were even more pronounced. Administration of a subcurative dose of TIOX to the rat produced in H. diminuta another change, the onset of which preceded the gross alterations in worm weight and chemical composition. In vitro studies, carried out 18 hr after treatment, revealed that TIOX-treated worms absorbed and metabolized much smaller quantities of exogenous glucose than did the controls and that the ability of the worm to accumulate glucose against a concentration difference was significantly depressed. A mode of action common to the structurally related benzothiazole and benzimidazole anthelmintics is indicated by the similarity of their biochemical and physiological effects on the tapeworms and their time course of action when administered to rats infected with H. diminuta. Molecular modeling revealed that the benzothiazole and benzimidazole anthelminitics are congruent electronically and structurally. In vivo drug efficacy depends upon the magnitude of the molecular dipole moment and the percentage of polar surface area. Within the benzimidazole series, structural and electronic congruence is found between the 2-thiazolyl and 2-methyl carbamate groups, suggesting that these groups behave similarly in transport to, and binding at, the active site. Finally, anthelmintics that have the 5' substituents twisted out-of-plane were more active than those anthelminitics with 5' substituents in-plane. All of these factors implicate a highly polar, L-shaped cleft to which the anthelmintics bind at the active site.

Animals↗

PubMed1990

Experimental and theoretical studies of albendazole, oxibendazole, and tioxidazole.

An investigation of the therapeutic effectiveness of albendazole (ABZ, methyl 5-[propylthio]benzimidazole-2-carbamate), oxibendazole (OBZ, methyl 5-[n-propoxy]benzimidazole-2-carbamate), and tioxidazole (TIOX, methyl 6-[n-propoxy]benzothiazole-2-carbamate) against Hymenolepis diminuta in experimentally infected rats is reported. All of the anthelmintics tested were effective therapeutically as a single oral dose against adult tapeworms, however, at different dose levels. The rank order of in vivo anthelmintic potency was ABZ greater than OBZ greater than TIOX. Molecular modeling revealed that drug efficacy depends on the orientation of the propyl group at position 5 on the heterocyclic ring system and on the magnitude of the molecular dipole moment.

Albendazole↗

PubMed1989

On the GABAA receptor: a molecular modeling approach.

Bicuculline methobromide, a complex alkaloid, antagonizes in some unknown manner the action of GABA, an important inhibitory transmitter in the CNS. To help understand the mechanism of this antagonism we have employed molecular modeling techniques to assess the similarity and difference between this antagonist and GABA plus four direct GABA agonists. Topological and electronic charge congruence between these five molecules was examined in great detail. It was found that each of the five molecules has three clearly defined atoms that serve as attachment points at the GABAA receptor site. It is hypothesized that an additional negatively charged atom on bicuculline serves as an additional point of attachment that blocks the nearby chloride ion channel. The model presented offers an explanation of why muscimol acts as a better agonist than GABA as well as rationalizing why (+)-bicuculline acts as an antagonist but (-)-bicuculline does not.

Bicuculline↗

PubMed1989

Experimental and theoretical studies of anthelmintics: oxfendazole and its imidazo[1,2-a]pyridine-2-carbamate isomer.

Mice experimentally infected with Trichinella spiralis were used to test the therapeutic effectiveness of an anthelmintic, methyl 6-(phenylsulfinyl)imidazo[1,2-a]pyridine-2-carbamate, against the immature and adult worms during the intestinal phase of infection. A single oral dose of 100 mg kg-1 of the drug on the third day after exposure to infection was totally ineffective against the adult worms as determined at necropsy on day 6. Neither higher unit dosages of the drug, division of the daily oral dose, nor increasing the length of the treatment period from 1 to 4 days enhanced drug activity in vivo. Furthermore the drug was inactive as a single oral dose against the immature worms at all of the dosages tested (12.5-400 mg kg-1). These results are in marked contrast to those obtained previously with oxfendazole (methyl 5[6]-(phenylsulfinyl)benzimidazole-2-carbamate) under comparable experimental conditions and clearly indicate that the two compounds are not anthelmintically equivalent in the T. spiralis-infected mouse system in spite of their similar structural features. A quantum mechanical study of these drugs was undertaken and a hypothesis for the inactivity of the imidazo[1,2-a]pyridine-2-carbamate isomer is proposed.

Animals↗

PubMed1987

Identification of a glycine-like fragment on the strychnine molecule.

Strychnine, a complex molecule, antagonizes in some unknown manner the action of glycine, an important inhibitory neurotransmitter in the spinal cord and brainstem of many vertebrates. To help understand the mechanism of this antagonism, we have employed modern computational methods to assess the similarities between these seemingly different molecules. An exhaustive comparison of topological and electronic features of both molecules was made. We have successfully located a glycine-like fragment in the strychnine molecule that, when compared to glycine, exhibits both topological and electronic charge congruence. The successful location of this glycine-like fragment allows us to speculate how the large strychnine molecule assumes its role as an antagonist against the inhibitory action of glycine, the simplest amino acid.

Animals↗

PubMed1984

Correlations between CNDO/2 charge distribution and 13C NMR chemical shift in 7-acylamino side chains of cephalosporins.

Molecular orbital calculations by the CNDO/2D method yield charge distributions which correlate well with the observed 13C NMR chemical shift for the amide carbon of acylamino side chains of cephalosporins. Acyl groups that withdraw electrons from the amide C-N bond and concomitantly make the amide nitrogen more negatively charged increase the chemical shift. The trends are related to the degree of amide resonance. No direct correlation was found between the chemical shift of the amide carbon and the antibacterial activity of the cephalosporins.

Carbon Isotopes↗

PubMed1982

Force field conformational analysis of aminofluorene and acetylaminofluorene substituted deoxyguanosine.

The hepatocarcinogen N-hydroxy-2-acetylaminofluorene forms two C8-substituted deoxyguanosine adducts in vivo. The conformation of these adducts, as well as 2'-deoxyguanosine and 8-amino-2'-deoxyguanosine has been studied with Allinger's force field. Using the glycoside rotation as a reaction coordinate, multidimensional potential energy surface were determined by relaxing all internal degrees of freedom. The calculations indicate the 2'-deoxyguanosine should exist as a mixture of syn and anti forms, that the syn form is slightly favored for 8-amino-2'-deoxyguanosine, that N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) will only be found in the syn conformation and that, although the syn form is also more stable for N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF), it will have a substantially greater proportion of the anti-conformer than is found with dG-C8-AAF. The results of the force field calculations are discussed in relation to the effects these adducts may have on DNA structure.

2-Acetylaminofluorene↗