Characterization of .alpha.-adrenoceptor populations. Quantitative relationships between cardiovascular effects initiated at central and peripheral .alpha.-adrenoceptors

Timmermans, Pieter B.M.W.M.; Jonge, A. de; Meel, J. C. A. Van; Slothorst-Grisdijk, Frieda P.; Lam, E.; Zwieten, P. A. van

doi:10.1021/jm00137a006

Cited by 37 publications

(9 citation statements)

References 4 publications

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“…In the present in vestigation. it would appear, therefore, that the large difference in intravenous potency between clonidine and St 1913 could be ac counted for by the large difference (66-fold) in the percentage of each compound existing in the un-ionized form, which is the form that will penetrate the relatively lipoidal blood-brain barrier [Timmermans et al, 1981], While a great deal of attention has been given to the physicochemical properties of aagonists that determine their rate of penetra tion into the central nervous system [Tim mermans el al.. 1977[Tim mermans el al.. , 1980[Tim mermans el al.. . 1981, little ef fort has been directed towards the factors that regulate diffusion out of the central ner vous system.…”

Section: Discussionmentioning

confidence: 99%

Receptor Interactions of Imidazolines

Rr¹,

El²,

Je³

et al. 1982

Pharmacology

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Clonidine and its methylene-bridged analog, St 1913, were potent α1 and α2 adrenergic agonists in vitro. The activity of each compound at each α-receptor subtype was similar indicating that changing the nitrogen bridge of clonidine to a methylene bridge (as in St 1913) does not markedly alter the pharmacology of the compound at the receptor level. This was confirmed in vivo by the fact that the pressor effects of both compounds in pithed rats, and the depressor effects in spontaneously hypertensive rats after intracisternal administration, were also similar. The α₂/α₁ selectivities of the compounds as assessed in vitro (ileum/aorta) and in vivo (pithed rat) were also similar to each other indicating that α-receptor subtype specificity is not greatly affected by changing the nitrogen bridge to a methylene bridge. Although no major differences were noted at the receptor level, significant changes in the physicochemical properties of the molecule were observed when the nitrogen bridge was changed to a methylene bridge. The pKa of clonidine was found to be 7.7 and that of St 1913 was 9.7. This corresponds to a large difference in the percent of each compound existing in the un-ionized species at physiological pH. Although both compounds exist predominantly in the ionized form at pH 7.4 (i.e., 67% for clonidine and 99.5% for St 1913), the percent existing in the un-ionized form is approximately 66 times greater for clonidine (33%) than for St 1913 (approximately 0.5%). While these differences in ionization (or un-ionization) did not influence drug effects at the receptor level, they did influence the overall pharmacology of the two compounds, and may account for large differences in antihypertensive potency between clonidine and St 1913. As a result, clonidine, which has similar activity as St 1913 at the receptor level, is approximately 25-fold more potent than St 1913 as an antihypertensive after intravenous administration to spontaneously hypertensive rats. Since both compounds possess equal abilities to lower blood pressure when administered beyond the blood-brain barrier (intracisternal administration), these results following intravenous administration indicate that clonidine penetrates the blood-brain barrier at a far greater rate than St 1913, and thereby more readily gains access to the site of action within the central nervous system. This, in turn, results from the greater percentage of clonidine existing in the un-ionized form relative to St 1913, and it is this un-ionized form which would more readily penetrate the blood-brain barrier. Likewise, the ability of these compounds to exit the brain via diffusion in the opposite direction through the blood-brain barrier is also influenced by the extent of ionization at physiological pH. Thus, clonidine, by virtue of existing in the un-ionized form to a greater extent than St 1913, will diffuse from the central nervous system into the periphery at a greater rate than St 1913. The results also indicate that while the un-ionized species more ...

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Section: Discussionmentioning

confidence: 99%

Receptor Interactions of Imidazolines

Rr¹,

El²,

Je³

et al. 1982

Pharmacology

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“…Timmermans and co-workers have published interesting series of papers about agonists and antagonists of adrenoceptors in order to characterization and classification of selected molecules (Timmermans et al , 1981 , 1984 ; Timmermans and Van Zwieten, 1982 ). In one of these papers (Timmermans et al , 1984 ), the authors have considered hypotensive and hypertensive activity relationships of α-adrenomimetics and experimentally determined logarithm of the n -octanol/water partition coefficient, log P , and also experimentally determined binding affinity to α 1 and α 2 receptors.…”

Section: Introductionmentioning

confidence: 99%

QSPR analysis of some agonists and antagonists of α-adrenergic receptors

2014

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Thirty-three compounds belonging to the sympatholytics and sympathomimetics were analyzed during the study. The biological activity data for the parameters of binding affinity to the α1- and α2-adrenergic receptors together with parameters of the logarithm of the partition coefficient n-octanol/water (log P) were performed using a semi-empirical calculations methods for isolated molecules (in vacuo) and for the molecules placed in an aqueous environment. Additionally, the chromatographic retention data were used as extra dependent variables of the structural parameters for a part of the considered compounds. Finally, all those groups of parameters were analyzed using MLR, PCA, and FA methods for the classification of studied compounds according to their chemical structures and pharmacological activity to the adrenoceptors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-014-1130-x) contains supplementary material, which is available to authorized users.

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“…The characteristic response to parenteral administration of an a2-adrenoceptor agonist is a short-lasting pressor response, due to stimulation of peripheral arterial postjunctional a 1-and az-adrenoceptors (Ruffolo et aL, 1982). The long-lasting hypotensive action probably results from stimulation of postsynaptic ~2-adrenoeeptors in the brainstem (Timmermans et al, 1981;Ruffolo et aL, 1993). Since a2-adrenoceptors have also been identified in the dorsal vagal nucleus (Dashwood et aL, 1985), it seems possible that az-agonists produce a direct action at this site to change vagal outflow (Ruffolo et al, 1993).…”

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confidence: 99%

Food intake and rumen motility in dwarf goats. Effects of atipamezole on the inhibitory effects induced by detomidine, medetomidine and romifidine

1994

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The effects of some alpha 2-adrenoceptor agonists and of the alpha 2-adrenoceptor antagonist atipamezole on food intake and ruminal contractions were studied in dwarf goats. Detomidine, 0.2 microgram/kg per min for 10 min, failed to modify food intake during either the first or second observation period (0-30 min and 180-210 min after drug infusion, respectively). Given at a higher dose rate (0.4 microgram/kg per min for 10 min), the drug inhibited food consumption during the first observation period, but stimulated food intake during the second period. A similar pattern was observed after IV infusion with medetomidine (0.2 microgram/kg per min for 10 min), romifidine (0.4 microgram/kg per min for 10 min) or xylazine (1 microgram/kg per min for 10 min). The alpha 2-antagonist atipamezole (2 micrograms/kg per min for 10 min) failed to modify food intake during either the first or second observation period. After treatment with atipamezole, the effects of alpha 2-agonists on feeding behaviour were completely antagonized. The alpha 2-agonists administered at similar dose rates to those used in the food intake experiments induced bradycardia, decreases in body temperature and inhibition of ruminal contractions. The inhibition of ruminal contractions induced by romifidine was partly antagonized by atipamezole pre-treatment. These findings demonstrate that the alpha 2-agonist-induced changes in ruminal contractions do not simply cause changes in feeding behaviour. The drop in body temperature induced by alpha 2-agonists was prevented by atipamezole pre-treatment, whereas the induced bradycardia was not modified by this alpha 2-antagonist.

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Characterization of .alpha.-adrenoceptor populations. Quantitative relationships between cardiovascular effects initiated at central and peripheral .alpha.-adrenoceptors

Cited by 37 publications

References 4 publications

Receptor Interactions of Imidazolines

Receptor Interactions of Imidazolines

QSPR analysis of some agonists and antagonists of α-adrenergic receptors

Food intake and rumen motility in dwarf goats. Effects of atipamezole on the inhibitory effects induced by detomidine, medetomidine and romifidine

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