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Biomedical subjects

R E Gibson

Publications and source records attributed to R E Gibson.

At least 73 records · Page 4Linked to original sources
PubMed1982

The use of tritium labeled compounds to develop gamma-emitting receptor-binding radiotracers.

In an effort to evaluate receptor binding drugs for their potential as gamma labeled radiopharmaceuticals suitable for clinical heart scanning, in vivo data were compared with the results obtained from a theoretical model. The distribution of selected tritium-labeled, receptor-binding radiotracers was studied in animals to determine if the heart to blood ratios agree with those obtained using a theoretical model of receptor binding. In general, the in vivo studies agree with the theoretical model when the concentration of the radiotracer in the heart is due to specific receptor binding. The use of the theoretical model for a first approximation followed by in vivo biodistribution studies is an efficient strategy to select those few from among the large number of receptor binding compounds that will ultimately yield an efficacious radiopharmaceutical to study receptor changes in the intact human heart.

Adrenergic alpha-Antagonists↗
PubMed1982

Analogues of 3-quinuclidinyl benzilate.

A number of analogues of 3-quinuclidinyl benzilate (QNB) have been synthesized and their affinities to muscarinic receptor from rat or dog ventricular muscle measured. We have determined that the muscarinic receptor can to a different degree accommodate either a halogen in the ortho, meta, or para position of one phenyl ring or the replacement of one phenyl ring with an alkyl group. Our in vitro competition studies show that the affinities lie within a 270-fold range, from the highest affinity compound, 3-quinuclidinyl alpha-hydroxy-alpha-cyclopentylphenylacetate (2), to the lowest affinity compound, 3-quinuclidinyl alpha-hydroxy-alpha-2-propargylphenylacetate (11).

Animals↗
PubMed1982

Three radioligands compared for determining cytoplasmic estrogen-receptor content of human breast carcinomas.

We compared three radioligands for use in a cytoplasmic estrogen-receptor assay, using pooled cytosol from human breast adenocarcinomas. The estrogen receptor content was determined in vitro by a dextran-coated charcoal method involving a 4-h incubation with and without diethylstilbestrol. Tritiated moxestrol failed to come to equilibrium in 4 h, thereby preventing the use of conventional one-component Scatchard analysis. The use of 125I-labeled estradiol resulted in a higher estimate of estrogen-receptor concentration than that obtained with use of tritiated estradiol. This overestimation was not corrected by Scatchard, double-reciprocal, or Woolf plots, or by two different methods of data analysis: least squared and "robust." An underestimation of the specific activity of iodoestradiol with respect to that of tritiated estradiol and an unrecognized second component of nonreceptor binding could explain this disparity.

Breast Neoplasms↗
PubMed1980

In vivo receptor binding of iodinated beta-adrenoceptor blockers.

Six radiolabeled beta-adrenoceptor blocking agents with a range of affinity constants were evaluated as radioindicators for adrenoceptors in guinea-pig heart and lung. All concentrated in the heart and lung at levels in excess of 0.1% dose/g tissue. On the basis of displacement studies using propranolol, two of the six compounds showed beta-adrenoceptor binding in the lung, and one, H-3 carazolol, showed receptor binding in the heart. These results agree qualitatively with a bi-molecular reversible equilibrium model, and suggest that the beta-adrenoceptor blockers as a group will not be useful in vivo probes of receptor concentration in the heart because of the low affinity constants and high levels of nonreceptor binding associated with the present-day clinical beta blockers. Beta-adrenoceptor blocking agents with affinity constants in excess of 10(9) will be needed to give heart-to-blood ratios of 10.

Adrenergic beta-Antagonists↗
PubMed1980

Radioiodinated estrogen derivatives.

Monoiodohexestrol exhibits 10 to 15% specific binding to the 8S estrogen receptor while the remainder binds to nonreceptor 4S proteins. Reduction of nonreceptor binding with either thyroxine or 8-anilino-1-naphthalene sulfonic acid was not quantitative. Thus no accurate determination of the concentration of receptor sites in the radioreceptor assay was possible by graphical analysis. Two additional estrogens--17 alpha [125I]iodoethynylestradiol and 17 alpha-[125I]iodoethynyl-11 beta-methoxy estradiol--were synthesized at high specific activity. Although the iodoethynyl derivatives were stable under synthetic conditions, deiodination in the presence of proteins is too fast to allow either in vivo or in vitro use. To make these compounds clinically useful, therefore, chemical modification to reduce nonreceptor binding and the rate of dehalogenation must be undertaken.

Anilino Naphthalenesulfonates↗
PubMed1979

Cardioselectivity of beta-adrenoceptor blocking agents 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols.

A series of 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols was synthesized together with several 1-[(3,4-dimethoxyphenethyl)amino]-3-(aryloxy)propan-2-ols. Their affinity to beta 1- and beta-2-adrenoceptors was determined and compared with the affinity of known beta-blockers. We were able to confirm the substantial cardioselectivity of 1-(3,4-dimethoxyphenethyl)-3-[(4-substituted aryl)oxy]propan-2-ols when compared to those with a 1-(4-hydroxyphenethyl) group. An increase in the size of the 4 substitutent of the 3-(aryloxy) moiety to caproamido leads to a substantially higher affinity for the beta 1--adrenoceptor of rat ventricular muscle in the presence of the 3,4-dimethoxyphenethyl than in the presence of the 4-hydroxyphenethyl or isopropyl group; this combination also gave the highest cardioselectivity.

Adrenergic beta-Antagonists↗
PubMed1979

The distribution of the muscarinic acetylcholine receptor antagonists, quinuclidinyl benzilate and quinuclidinyl benzilate methiodide (both tritiated), in rat, guinea pig, and rabbit.

The distribution of [3H]quinuclidinyl benzilate and its methiodide salt was determined in rat, guinea pig, and rabbit. Accumulation in the myocardium of up to 2% of the injected dose per gram of tissue was obtained with both compounds, providing heart-to-blood ratios of approximately 30 and heart-to-lung ratios of approximately 4. The accumulation in the heart was blocked (89%) by preinjection of atropine. The distribution of tritium in rabbit heart corresponds to the muscarinic receptor densities determined in vitro. Calculation of the theoretical maximum for the bound-to-free ratio, based on in-vitro equilibrium binding isotherms, resulted in ratios in reasonable agreement with the experimental results. Because of the high accumulation in the heart with low serum concentration, we conclude that the methiodide salt of quinuclidinyl benzilate represents an ideal parent structure for the design of a receptor-binding gamma-emitting radiopharmaceutical for imaging of the myocardium.

Acetylcholine↗
PubMed1978

Radioiodinated derivatives of beta adrenoceptor blockers for myocardial imaging.

Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their I-125-tagged derivatives evaluated in rats. This distribution was compared with the distribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clearance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardioselectivity were diminished. An inverse correlation is suggested between the dissociation constant for the beta adrenoceptor in the lung and the heart-to-blood and heart-to-lung values. We conclude that polarity plays an important role in the blood clearance and cardioselectivity of these beta-adrenoceptor derivatives.

Adrenergic beta-Antagonists↗
PubMed1977

Study of trans-cyclopropylbis (diketopiperazine) and chelating agents related to ICRF 159. Cytotoxicity, mutagenicity, and effects on scheduled and unscheduled DNA synthesis.

The cytotoxicity, mutagenicity, and DNA damaging potential of trans-cyclopropylbis (diketopiperazine) (3) and chelating agents related to ICRF 159 (1) were examined as a function of concentration and duration of exposure in the Chinese hamster cell line V79A. At a concentration of 10(-3) M, 1 and the trans-cyclopropanediamine tetraacid 8 and ester 7 proved to be cytotoxic and mutagenic. The trans-cyclopropyl analogue 3 of ICRF 159 and acyclic tetraacid 6 were less cytotoxic at all concentrations; analogue 3 exhibited no mutagenic activity at any of the concentrations tested. Compounds 1, 7, and 8, at lethal concentrations, exhibited significantly different mutation frequencies with 7 being sixfold more mutagenic than 8 at the same molar concentration. At 10(-3) M compounds 8 was several times more effective blocking DNA replication than other analogues but did not induce unscheduled DNA synthesis as did 1,3, and 6. With the exception of 8, there was an excellent correlation between mutagenesis and the induction of unscheduled DNA synthesis.

Animals↗
PubMed1977

Distinctions between the two-state and sequential models for cooperative ligand binding.

The two-state and sequential models for positive cooperativity in ligand binding can produce significantly different theoretical binding curves when presented in a Scatchard plot. The conditions that produce the greatest differences have been examined. The theoretical differences have been used to select the two-state model as the best model for describing the binding of acetylcholine to acetylcholine receptors that have been solubilized by Triton X-100 and sodium cholate.

Acetylcholine↗