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T Bultsma

Publications and source records attributed to T Bultsma.

10 recordsLinked to original sources
PubMed1988

Mapping of the beta 2-adrenoceptor on Chang liver cells. Differences between high- and low-affinity receptor states.

Receptor mapping procedures based on the methodology of Crippen are used to study the beta 2-adrenergic receptor system in intact Chang liver cells. In cases of agonists, the presence of both a low- and high-affinity receptor state is assumed, whereas antagonists bind to the low-affinity state only. The high-affinity state is considered to contain the "functional" binding site responsible for formation of the second messenger (cAMP), whereas the low-affinity state is assumed to be the "true" (physiological) low-affinity state. Both receptor states are taken into account in the receptor mapping process. Characterization of the high- and low-affinity states made it possible to identify features that make a state an antagonist or agonist. The receptor model found for the low-affinity state of the beta-adrenergic receptor present in an intact cell system is compared to the low-affinity state previously obtained for this receptor present on a membrane preparation of the bovine skeletal muscle in the presence of high amounts of Gpp(NH)p guanosine 5'-(beta, gamma-imidotriphosphate). Remarkable differences are found between the two receptor models. The tentative conclusion is drawn that these differences in low-affinity states most probably are artificial and are caused by the different pharmacological properties (e.g., intrinsic activity) of the labeled ligands used in displacement experiments for determining the affinities of the drugs.

Cell Membrane↗
PubMed1986

Mapping the turkey erythrocyte beta receptor: a distance geometry approach.

Extensions and refinements of the receptor mapping method as originally developed by Crippen are presented. In a set of newly developed algorithms measures are taken to reduce the number of required energy parameters to a statistically acceptable degree. The most important measure is the incorporation of lipophilicity as a hydrophobic bonding parameter to describe the binding of parts of the ligands to lipophilic areas on the receptor. In order to test the applicability of our set of programs, we mapped the turkey erythrocyte beta receptor using a data set of Bilezikian. It was found that the experimentally determined free energies of binding can be reasonably described using a nine-point geometrical representation of the receptor site and only six energy parameters. The deduced model predicts that the phenyl rings of phenylethanolamines and phenoxypropanolamines occupy different parts of the receptor site.

Animals↗
PubMed1986

Quantitative evaluation of the beta 2-adrenoceptor intrinsic activity of N-tert-butylphenylethanolamines.

The extent of stimulation of the enzyme adenylate cyclase, and the concomitant production of cAMP, by a number of beta-adrenoceptor agonists, all belonging to the class of the N-tert-butylphenylethanolamines, has been determined. The results have been used as direct measures for intrinsic sympathomimetic activity (ISA) and were correlated with various physicochemical parameters of the compounds. Significant correlations were established by means of the method of multiple regression analysis, and it was demonstrated that electronic effects only govern ISA. The use of 13C NMR chemical shifts of the aromatic C atoms proved to be a valuable tool in this analysis.

Adrenergic beta-Agonists↗
PubMed1986

Binding characteristics of the regulatory guanine nucleotide binding protein, and the activation of the enzyme adenylate cyclase, present in a bovine skeletal muscle membrane preparation.

The binding of [3H]GppNHp (beta, gamma-imido[8(-3)H] guanosine 5'-triphosphate) to membrane particles of a bovine skeletal muscle preparation, the m.trapezius, and the subsequent activation of adenylate cyclase in this preparation have been studied, both in the presence and absence of (-)-isoprenaline. Specific binding of [3H]GppNHp could be best explained on the assumption of a two-sites model, in which the binding sites displaying the higher affinity, appeared to be associated with the activation of adenylate cyclase, and are likely to include the regulatory guanine nucleotide binding protein (G/F or NS). The apparent excess of high affinity [3H]GppNHp binding sites over the number of beta-adrenoceptors in this preparation with respect to its possible physiological relevance is discussed.

Adenylyl Cyclases↗
PubMed1985

Factors controlling beta 1-adrenoceptor affinity and selectivity.

A membrane preparation of the calf heart left ventricle has been used after identification and characterization, as a source of myocardial beta 1-adrenoceptor for radioligand binding studies. The displacement of specifically bound (-)-[3H]dihydroalprenolol by some beta-adrenoceptor ligands appeared to be pH-dependent, which could be related to the ionization characteristics of the compounds. Among the usually four ionic species of the ligand, present at physiological pH, the cation was shown to govern beta 1-adrenoceptor affinity. Furthermore, quantitative structure affinity relationships for the interaction with beta 1- and beta 2-adrenoceptors were established for the phenoxypropanolamines, a class of beta-adrenoceptor ligands. The N-isopropyl-oxypropanolamine side chain itself does not discriminate between beta 1- and beta 2-adrenoceptors, whereas aromatic substitution ortho to the side chain induces some beta 2-selectivity. Selectivity for myocardial beta 1-adrenoceptors is mainly obtained by aromatic substitution para to the side chain. This substitution pattern yields a decrease in beta 2-adrenoceptor affinity, far more pronounced than the decrease in beta 1-adrenoceptor affinity.

Animals↗
PubMed1985

Quantitative evaluation of the beta 2-adrenoceptor affinity of phenoxypropanolamines and phenylethanolamines.

The influence of the aromatic moiety of beta-adrenoceptor ligands on the affinity for the beta 2-adrenoceptor has been studied. Three classes of ligands have been examined, viz. N-isopropyl- and N-tert-butylphenylethanolamines and N-isopropylphenoxypropanolamines. Computer-assisted analysis of the inhibition by any of these ligands of the specific (-)-[3H]dihydroalprenolol binding to the beta 2-adrenoceptors of a bovine skeletal muscle preparation in the presence of GppNHp (10(-4) M) yielded the affinities of these ligands at pH 7.5. The obtained values were adjusted for the amounts of cations present at this pH value. A significant correlation was found between the calculated lipophilicities and the experimentally determined affinities in the three classes. Furthermore, steric factors seem to play an important role, as these correlations were improved by the introduction of steric parameters for the aromatic substituents in the regression analyses. From the established equations it is concluded that the phenoxypropanolamine derivatives bind to the beta 2-adrenoceptor in a way different from that of the ligands in both ethanolamine classes.

Animals↗
PubMed1984

The relation between ionization and affinity of beta-adrenoceptor ligands.

The displacement by some beta-adrenoceptor ligands of the specific (-)-[3H]dihydroalprenolol binding to membranes of the bovine musculus trapezius, a rich and homogeneous source of beta 2-adrenoceptors, appeared to be pH-dependent. This phenomenon was in contrast to the pH-dependency of the (-)-[3H]dihydroalprenolol receptor-binding and could be related to the ionization characteristics of the compounds. It was shown quantitatively that of the four ionic species of the ligands commonly present at physiological pH, the cation governs beta 2-adrenoceptor affinity.

Animals↗
PubMed1984

The ionization of beta-adrenoceptor agonists: a method for unravelling ionization schemes.

To investigate the ionization schemes of beta-adrenoceptor agonists, a combined electrochemical/uv-spectrophotometric method with computer-assisted data-analysis was developed, yielding the macroscopic and microscopic ionization constants. From the four species possible, cations and zwitterions were found the main species present at physiological pH, the formation of uncharged molecules and anions being less favourable or apparently negligible.

Adrenergic beta-Agonists↗
PubMed1979

Determination of erythrocyte membrane-buffer partition coefficients by numerical analysis of multicomponent spectra.

A method suitable for the measurement of erythrocyte membrane-buffer partition coefficients by u.v.-spectrophotometry is described. This method is characterized by a proper correction for inconstant background absorption in case of bad signal to noise ratios. For this purpose the multicomponent u.v.-spectrum of a compound in the presence of absorbing materials lost by erythrocyte membranes is decomposed into its constituent spectra by means of numerical analysis. Application of this method to the determination of partition coefficients of benzhydrol, 4-bromophenol and benzyl alcohol yields satisfactory agreement with literature values for the latter two coefficients.

Benzhydryl Compounds↗