Receptor Occupancy and Tissue Response

Nickerson, Mark

doi:10.1038/178697b0

Cited by 246 publications

(100 citation statements)

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“…Stephenson (1956) has pointed out that if there is a receptor reserve a lowered activity may be due to either of these causes. The most satisfactory method yet described for evaluating the receptor reserve is the use of the irreversible antagonist dibenamine, introduced by Nickerson (1956) for studying receptor reserves of catechol amine receptors and applied by van Rossum & Ariens (1962) and others to assessment of the reserves of acetylcholine and histamine receptors. We have used the method of these authors, with acetylcholine as the agonist.…”

Section: Resultsmentioning

confidence: 99%

The Role of Ionic Interaction at the Muscarinic Receptor

Burgen

1965

British Journal of Pharmacology and Chemotherapy

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It is commonly assumed by pharmacologists that the positively charged cationic group in such agonists as acetylcholine, noradrenaline and histamine is essential for their agonist action. The evidence in favour of this view is far from conclusive. Barlow & Hamilton (1962) examined the effect ofpH on the activity of nicotine in producing synaptic block of the rat phrenic nerve-diaphragm preparation. When compared with the quaternary nicotine N-methiodide the activity of nicotine was related to thepH in the way to be expected if the nicotinium ion were more active than the non-protonated form, but neither the range ofpH values studied nor the precision of the results were sufficient to establish the activity (if any) of the non-protonated nicotine relative to the nicotinium ion. Hamilton (1963) has shown a similar effect of pH in the action of nicotine on the frog rectus abdominus muscle, but in this case also the activity of the non-protonated form was not established. Ariens, Simonis & van Rossum (1964) were unable to discover any clear relationship between pH and the action of arecoline on the frog rectus, but did not extend their study over a wide enough pH range to obtain decisive results. Rocha e Silva (1961) examined the effect ofpH on the action of histamine. There was a clear pH-dependence below pH 7 but the action was independent of pH above 7. These results are compatible with the response to histamine being dependent on a group with a pKa 7.0. However, since the dissociation constants of the ionizable groups in histamine are pKaj, 5.9; pKa2, 9.7, the pH-dependence cannot be attributed to the change in histamine ionization and is probably due to a change in the charge on the receptors.An alternative approach to the problem is to study the activity of analogues of the agonist in which the basic nitrogen atom has been replaced by an atom with a different electron shell so that a cation is not formed. Banister & Whittaker (1951) examined the action of 3,3-dimethylbutyl acetate, the analogue of acetylcholine in which the basic nitrogen atom has been replaced by a carbon atom. On the frog rectus, this drug had about 1/12,000th the activity of acetylcholine and, on the guinea-pig ileum, the activity was small and maximal responses were not obtained. The analogue of histamine in which the primary amino-group is replaced by a hydroxyl group, H-(2-hydroxyethyl)-imidazole, is reported to have little or no histamine-like activity (Vartiainen, 1935;Schneedorf & Ivy, 1935;Grossman, Robertson & Rosiere, 1952). These latter pieces of evidence do suggest that uncharged analogues may have some activity and it seemed that the problem merited further examination in view of its importance for the theoretical interpretation of drugreceptor interactions.

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Section: Resultsmentioning

confidence: 99%

The Role of Ionic Interaction at the Muscarinic Receptor

Burgen

1965

British Journal of Pharmacology and Chemotherapy

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“…However, Furchgott (1955) and Nickerson (1956) demonstrated that s-haloalkylamines can produce a paralle', shift to the right of the concentration-response curves of various agonists before any decline in the maximal response is observed. Similar results were reported later by Gill and Rang (1966) for the antagonism by benzylylcholine mustard (BCM) against acetylcholine on intestine and by Burgen and Spero (1968) for antagonism by BCM of both the contraction of smooth muscle and the increase of K+ and Rb++ efflux produced by carbachol.…”

Section: General Introductionmentioning

confidence: 99%

“…Similar results were reported later by Gill and Rang (1966) for the antagonism by benzylylcholine mustard (BCM) against acetylcholine on intestine and by Burgen and Spero (1968) for antagonism by BCM of both the contraction of smooth muscle and the increase of K+ and Rb++ efflux produced by carbachol. Such findings were interpreted to indicate the presence of "spare" receptors (Furchgott, 1955;Nickerson, 1956;Stephenson, 1956; Ariëns et a 1 _", 1960). A 100-fold inhibition of the histamine response in the guinea-pig ileum by a s-haloalkylamine occurred without any decrease in the maximal response (Nickerson, 1956), indicating that as few as 1 % of the total receptors may suffice to produce a maximal response.…”

Section: General Introductionmentioning

confidence: 99%

“…Such findings were interpreted to indicate the presence of "spare" receptors (Furchgott, 1955;Nickerson, 1956;Stephenson, 1956; Ariëns et a 1 _", 1960). A 100-fold inhibition of the histamine response in the guinea-pig ileum by a s-haloalkylamine occurred without any decrease in the maximal response (Nickerson, 1956), indicating that as few as 1 % of the total receptors may suffice to produce a maximal response. This clearly invalidates the above assumption of Clark, and several attempts have been made to eliminate it from treatments of drug-receptor interactions.…”

Section: General Introductionmentioning

confidence: 99%

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Transformation of Adrenergic Receptors in the Myocardium

1973

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·ABSTRACTThe present series of experiments provided evidence that the generally accepted distinction between a-and s-adrenergic receptors is not immutable. In frog hearts and rat atria 3H-phenoxybenzamine (3H-POB ) blocked inotropic responses to catecholamines only at temperatures below l7 0 C and potentiated responses ab ove 23 0 C, and considerably more radioactivity was bound to the myocardium at lower temperatures. The converse was true for l4C-propranolol, and the potency of a-and s-adrenergic agonists was shawn to parallel the effectiveness of the blocking agents. Alkylation of a-adrenergic receptors by POB at l4 0 c prevented the appearance of s-adrenergic receptors when the temperature was subsequently raised ta 24 o C.Phentolamine prevented block by 3H-POB and considerably reduced its binding ta the myocardium at low but not at high temperatures. After exposure ta unlabelled POB in the presence of phentolamine at low temperature and thorough washing, exposure to 3H-POB produced a IIpositive label" of the adrenergic receptors, which was localized in a 20,000 9 (ll mitochondrial ll ) and in a IIsoluble protein" fraction. Pretreatment of rats with 6-hydroxydopamine, but not with reserpine, prevented the appearance of oe-adrenergic receptor charac.teristics in left atria at low temperatures; this indicated that adrenergic innervation, but probably not stores of neurotransmitter, is necessary to allow transformation of the receptors. It is suggested that a-and S-adrenergic receptors may be different allosteric conformations of the same molecule.

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“…It is well known that the dose response curve of the agonist for which there are spare receptors shifts in parallel with application of an irreversible blocker of these receptors (5,6). In this paper we observed parallel shifts in the dose response curves of all the a-adrenoceptor stimulants after the progressive incubation of the guinea pig taenia caecum with dibenamine ( Fig.…”

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confidence: 99%

A receptor reserve of the alpha-inhibitory receptor for alpha-adrenoceptor stimulants in the taenia caecum of guinea pig.

Takayanagi

Kizawa

1980

Jpn.J.Pharmacol

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Adrenoceptors were classified as a and (9-receptors by Ahlquist (1). The a-receptor is generally associated with the excitatory functions and the a-receptor with the inhibitory functions in various smooth muscles. Stimulation of the a and (3-receptors in intestinal smooth muscles produces a relaxation (2). Our knowledge of the receptor reserve of a-receptor for the a-adrenoceptor stimulants has been, however, obtained from data in the excitatory responses (3, 4). Little is known of the receptor reserve for the a-agonists in inhibitory mechanisms.Male guinea pigs, weighing 300 to 400 g, were sacrificed by a blow on the neck and a piece (3 to 4 cm) of taenia was removed from the caecum and suspended in a 20 ml organ bath filled with Locke Ringer's Solution (NaC1 154, KCl 5.6, CaC12 2.2, MgC12 2.1, NaHCO3 5.9 and glucose 2.8 mM) kept at 37'C and bubbled with air. The physiological solution also contained propranolol hydrochloride (3 x 10-6 M) which blocks the (3-adrenoceptor action of a-adrenergic stimulants. Norepinephrine hydrochloride, epinephrine bitartarate and phenylephrine hydrochloride were used as a-adrenoceptor stimulants and dibenamine

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Receptor Occupancy and Tissue Response

Cited by 246 publications

References 1 publication

The Role of Ionic Interaction at the Muscarinic Receptor

The Role of Ionic Interaction at the Muscarinic Receptor

Transformation of Adrenergic Receptors in the Myocardium

A receptor reserve of the alpha-inhibitory receptor for alpha-adrenoceptor stimulants in the taenia caecum of guinea pig.

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