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Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 199 records · Page 11Linked to original sources
PubMed1983

Differences in the applicability of the easson-stedman hypothesis to the alpha 1- and alpha 2-adrenergic effects of phenethylamines and imidazolines.

The enantiomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, were evaluated at alpha 1- and alpha 2-adrenergic receptors to test the applicability of the Easson-Stedman hypothesis to the imidazoline class of alpha-adrenergic agonists. A series of closely related phenethylamines was included for comparison. The Easson-Stedman hypothesis states that optically active adrenergic agonists possessing an asymmetric hydroxyl-substituted benzylic carbon atom will have the following relative potencies: R(-) greater than S(+) = desoxy. While the phenethylamines were found to adhere to the Easson-Stedman hypothesis at both alpha 1- and alpha 2-adrenergic receptors, the optically active imidazolines did not. These findings further support our previous observations that the phenethylamines and imidazolines may interact differently with alpha-adrenergic receptors.

Animals↗
PubMed1983

Blockade and postjunctional vascular alpha 1- and alpha 2-adrenoceptors in pithed rat by the enantiomers of WB-4101.

The enantiomers of WB-4101 were evaluated for their ability to antagonize the alpha 1-adrenoceptor mediated pressor effect of cirazoline and the alpha 2-adrenoceptor mediated pressor effect of UK-14,304 in pithed rats. The (S)-stereoisomer of WB-4101 was more potent than the enantiomeric (R)-isomer in antagonizing both cirazoline and UK-14,304. The difference in potency between the enantiomers in blocking cirazoline was 37-fold in contrast to an enantiomeric difference of less than 3-fold for antagonizing UK-14,304. Based on DR2 values (i.e., dose of WB-4101 isomer in mg/kg required to produce a 2-fold rightward shift in the dose-response curves of cirazoline and UK-14,304) obtained in vivo from Schild regressions, alpha 1/alpha 2 selectivity ratios were calculated. While the (S)-enantiomer displays a 187-fold selectivity for alpha 1-adrenoceptors, the (R)-enantiomer is only approximately 13-fold selective for alpha 1-adrenoceptors. These results indicate that the alpha 1- and alpha 2-adrenoceptor blocking activity of WB-4101 resides predominantly in the (S)-enantiomer and that both enantiomers of WB-4101 are selective alpha 1-adrenoceptor antagonists in vivo. However the degree of alpha 1-adrenoceptor selectivity differs from each enantiomer, and the enantiomeric activity ratios differ for each alpha-adrenoceptor subtype.

Adrenergic alpha-Antagonists↗
PubMed1983

Antinociceptive activity of N-(4-hydroxyphenacetyl)-4-aminoclonidine, a novel analog of clonidine: role of opioid receptors and alpha-adrenoceptors.

N-(4-hydroxyphenacetyl)-4-aminoclonidine, a derivative of the alpha-adrenoceptor agonist p-aminoclonidine, was found to exhibit dose-dependent antinociceptive activity in the mouse writhing assay. In this measure of antinociceptive activity it was less potent than clonidine or xylazine. Naloxone, an opioid receptor antagonist, at a dose sufficient to abolish the antinociceptive activity of morphine, did not affect the antinociceptive activity of N-(4-hydroxyphenacetyl)-4-aminoclonidine, clonidine or xylazine. In contrast, yohimbine, a alpha-adrenoceptor antagonist, reduced the antinociceptive activity of N-(4-hydroxyphenacetyl)-4-aminoclonidine, clonidine and xylazine, but not morphine. The affinity of N-(4-hydroxyphenacetyl)-4-aminoclonidine, clonidine and xylazine for alpha-adrenoceptors in rat aorta was correlated highly with the relative potency for writhing inhibition. These results suggest that the antinociceptive activity of N-(4-hydroxyphenacetyl)-4-aminoclonidine is mediated by alpha-adrenoceptors.

Analgesics↗
PubMed1983

Interaction of clonidine, its methylene-bridged analog, St 1913, and the benzylic hydroxyl-substituted derivative, St 1965, with alpha 1- and alpha 2-adrenoreceptors.

The effects of benzylic hydroxyl substitution on the activity of a close structural analog of clonidine was assessed at alpha 1- and alpha 2-adrenoreceptors both in vitro and in vivo in order to uncover possible differences that this substitution may have on the effects of imidazolines and phenethylamines at adrenoreceptors. In all test systems, the presence of the benzylic hydroxyl group was associated with a consistent and marked decrease in activity. These findings are in agreement with our previous studies with imidazolines having different pharmacological profiles and different physicochemical properties than the clonidine derivatives reported herein. We conclude, therefore, that the deleterious effects of the benzylic hydroxyl group is ubiquitous among imidazolines and, more importantly, is in marked contrast to the 100-1000 fold enhancement in activity that the benzylic hydroxyl substituent (i.e. beta-hydroxyl group) produces for the phenethylamines. The results support the concept that imidazolines and phenethylamines may interact differently with alpha-adrenoreceptors.

Adrenergic alpha-Agonists↗
PubMed1982

Stereochemical requirements of alpha 2-adrenergic receptors for alpha-methyl substituted phenethylamines.

The alpha 1- and alpha 2-adrenergic effects of the stereoisomers of alpha-methyldopamine were evaluated in guinea pig aorta and field-stimulated guinea pig ileum, respectively, in order to establish the stereochemical requirements of these receptors for alpha-methyl substituted phenethylamines. The alpha 1-adrenergic receptor did not distinguish between the stereoisomers of alpha-methyldopamine which is in marked contrast to the alpha 2-adrenergic receptor where a dramatic stereochemical preference for the 2S(+)-isomer was observed. In addition, 2R(-)-alpha-methyldopamine displayed no alpha-receptor subtype specificity whereas 2S(+)-alpha-methyldopamine was highly selective (23 fold) for the alpha 2-adrenergic receptor. These results indicate that the alpha 2-adrenergic receptor can recognize and accept methyl substituents at the alpha-carbon atom of phenethylamines when correctly oriented, while the alpha 1-adrenergic receptor cannot. Thus, the alpha-carbon atom is a major determinant of the alpha 2-adrenergic effects of phenethylamines, and plays an important role in determining alpha-receptor subtype specificity. It is hypothesized that the alpha 2-adrenergic receptor (but not alpha 1) has an additional recognition site which will accommodate alpha-substituted phenethylamines.

Animals↗
PubMed1982

Receptor interactions of imidazolines: alpha-adrenoceptors of rat and rabbit aortae differentiated by relative potencies, affinities and efficacies of imidazoline agonists.

1 Noradrenaline and a series of imidazolines were used to characterized and differentiate the postsynaptic alpha-adrenoceptors of rat and rabbit aortae. 2 Dose-response curves in each tissue revealed marked differences in the profile of agonist activity among the compounds. Based on the ED50 values for each compound, a rank order of potency of oxymetazoline greater than noradrenaline greater than tramazoline greater than tetrahydrozoline greater than clonidine was obtained in rabbit aorta and an order of noradrenaline greater than clonidine greater than tramazoline greater than oxymetazoline was obtained in rat aorta. Tetrahydrozoline had no agonist activity in rat aorta. 3 Dissociation constants were determined for each agonist in rat and rabbit aortae. Again, differences between the tissues were observed to the extent that the rank order of affinities for the imidazolines were exactly opposite for the two tissues. In rabbit aorta the order was, oxymetazoline greater than tramazoline greater than tetrahydrozoline greater than clonidine, whereas in rat aorta it was, clonidine greater than tetrahydrozoline greater then tramazoline greater than oxymetazoline. The extremes in tissue selectivity were observed with clonidine, which had approximately 125 fold higher affinity in rat aorta, and oxymetazoline, which had approximately 4 times higher affinity in rabbit aorta. 4 The absolute values of relative efficacies of the imidazolines studied, and their rank order, also differed between the two tissues. The relative efficacies of oxymetazoline and tramazoline were more than 15 fold greater in rabbit aorta than in rat aorta. Furthermore, tetrahydrozoline had a greater relative efficacy than clonidine in rabbit aorta while the converse was true in rat aorta. 5 Differences in the rank order of potency, affinity and relative efficacy of noradrenaline and a series of imidazolines in rat and rabbit aortae indicate that the postsynaptic alpha-adrenoceptors in these tissues are different. While the postsynaptic alpha-adrenoceptor of rabbit aorta is clearly of the alpha 1-subtype, the exact nature of the postsynaptic alpha-receptor of rat aorta is not clear. The unique alpha-receptor of rat aorta has properties of both alpha 1- and alpha 2-adrenoceptors.

Animals↗
PubMed1982

Receptor interactions of imidazolines. IX. Cirazoline is an alpha-1 adrenergic agonist and an alpha-2 adrenergic antagonist.

The alpha-1 and alpha-2 adrenergic effects of cirazoline were evaluated in guinea-pig aorta and field-stimulated guinea-pig ileum, respectively. Cirazoline was found to be a full agonist at alpha-1 receptors having an ED50, dissociation constant (KA) and relative efficacy similar to that of (-)-norepinephrine. In contrast, cirazoline does not possess agonist activity at presynaptic alpha-2 receptors in the guinea-pig ileum. Thus, whereas norepinephrine and cirazoline both inhibited the twitch response of the field-stimulated ileum, only the response to norepinephrine was blocked by the selective alpha-2 antagonist, yohimbine. The nonadrenergic inhibition of the twitch response observed in the ileum with cirazoline resulted from weak anticholinergic activity (antimuscarinic) at the level of the postsynaptic effector organ and was observed only at high concentrations. At concentrations far below the level required to inhibit the twitch response, cirazoline was found to competitively antagonize the alpha-2-mediated inhibition of the twitch response elicited by norepinephrine. A Schild plot analysis indicated that cirazoline is a potent competitive alpha-2 receptor antagonist characterized by a pA2 value (i.e., -log KB) of 7.56. These results indicate that cirazoline is unique among imidazolines in that it is a potent alpha-1 adrenergic receptor agonist and an even more potent alpha-2 receptor antagonist. This unusual combination of activities could make cirazoline a particularly effective vasoconstricting agent.

Adrenergic alpha-Agonists↗
PubMed1982

Conformational requirements of alpha 2-adrenergic receptors.

The conformationally restrained trans-extended and cis-folded isomers of 2-(3,4-dihydroxyphenyl)cyclobutylamine were used to establish the conformational requirements of presynaptic alpha 2-adrenergic receptors in the field-stimulated guinea pig ileum. The trans-extended isomer produced a concentration-dependent inhibition of the twitch response with an EC50 of 34 microM. The cis-folded analogue failed to produce a significant inhibition of the twitch response at concentrations up to 1 mM. These results suggest that the presynaptic alpha 2-adrenergic receptor prefers phenethylamines in the trans-extended conformation over the cis-folded conformation. The conformational requirements of alpha 1- and alpha 2-adrenergic receptors appear to be similar.

Animals↗