Differences in affinities of muscarinic acetylcholine receptor antagonists for brain and heart receptors.

The affinities of atropine, scopolamine, 3-quinuclidinyl benzilate and twelve analogues of 3-quinuclidinyl benzilate were determined for the muscarinic acetylcholine receptor (m-AChR) using membrane preparations from caudate/putamen. The affinity constants thus obtained were compared with affinities previously reported for the m-AChR obtained from ventricular muscle. The affinities differed significantly for six of the compounds, the largest difference being 16-fold.

Cardioselectivity of beta-adrenoceptor blocking agents. 2. Role of the amino group substituent.

A series of 1-(aralkylamino)-3-(aryloxy)propan-2-ols were synthesized, and their apparent dissociation constants (Kapp) were determined by using rat ventricular muscle (RVM) and rat lung membrane (RLM) preparations. Analysis of the binding studies suggests the existence of different modes of binding dependent on the presence or absence of the 4-substituent in the aryloxy ring and the nature of that ring. Without 4-substitution only one compound (4), bearing the 2-(2-methoxyphenoxy)ethyl substituent on the amino group, shows high cardioselectivity.

In vivo chemistry of 99mTc-chelates.

The structure-activity relationships involved in the in vivo localization and clearance of 99mTc-chelates is reviewed. Most 99mTc-chelates used for renal studies are mixed function agents and their uptake in the kidney is affected by the presence or absence of stannous ions; only a relatively few chelates are almost exclusively cleared from the body by glomerular filtration or tubular excretion. The uptake of 99mTc-phosphates and -phosphonates in metabolically active and metabolically inactive bone and the plasma clearance rate of these complexes depend upon the structure of the complexing ligand.

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).

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 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.

Radiolabeling of antibodies.

The radiolabeling of antibodies is considered in terms of the choice of radionuclide, the method of conjugation, and the effect of conjugation on plasma clearance. Iodination techniques are reviewed, but the major emphasis is placed on the methods of conjugating metallic radionuclides using bifunctional chelating agents. The technique of producing clinically useful radiolabeled antibodies by balancing altered substrate specificity caused by radiolabeling against accelerated plasma clearance is discussed.

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.

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.

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.

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.

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.

Estrogen derivatives for the external localization of estrogen-dependent malignancy.

Four radioiodinated estrogen derivatives were studied to determine their affinity for the estrogen-binding protein found in the cytosol of rabbit and rat uteri. In vitro determination of the binding properties by competitive-binding experiments and by sucrose-gradient centrifugation indicates that one of the derivatives, iodohexestrol, binds to the cytosol estrogen-binding protein. This in vitro behavior was related to in vivo distribution.

Biological distribution of chemical analogs of fatty acids and long chain hydrocarbons containing a strong chelating agent.

The pharmaceutical preparation, chromatography, and biological distribution of a series of new chemical analogs of palmitic acid and diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, or diethylenetriamine are described. The biological distribution in rabbits 30 min after intravenous administration of these 99mTc-labeled and 57Co-labeled derivatives was compared to the biological distribution of the parent compound, 3H-palmitic acid. The average myocardial uptake for these compounds was 0.