A Modification of Receptor Theory

Stephenson, R. P.

doi:10.1111/j.1476-5381.1956.tb00006.x

Cited by 799 publications

(311 citation statements)

References 14 publications

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“…Our data demonstrate that moxonidine behaves as a partial, or less efficacious (39), agonist at ␣ 2A -AR, and serves as a prototype for agents capable of selectively modulating cardiovascular responses without sedative side effects. Focusing on the development of ␣ 2A -AR partial agonists of differing relative efficacy could lead to refined strategies for treatment of attentional focus in attention deficit hyperactivity disorder (12,16) or enhancement of cognition in the elderly (12).…”

Section: Discussionmentioning

confidence: 99%

Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Tan

Wilson

MacMillan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Genetic manipulation of the ␣2A-adrenergic receptor (␣2A-AR) in mice has revealed the role of this subtype in numerous responses, including agonist-induced hypotension and sedation. Unexpectedly, ␣2-agonist treatment of mice heterozygous for the ␣2A-AR (␣2A-AR ؉/؊ ) lowers blood pressure without sedation, indicating that more than 50% of ␣2A-AR must be activated to evoke sedation. We postulated that partial activation of ␣2A-AR in wild-type ␣2A-AR ؉/؉ animals could be achieved with partial agonists, agents with variable ability to couple receptor occupancy to effector activation, and might elicit one versus another pharmacological response. In vitro assays reveal that moxonidine is a partial agonist at ␣2A-AR. Although moxonidine was developed to preferentially interact with imidazoline binding sites, it requires the ␣2A-AR to lower blood pressure because we observe no hypotensive response to moxonidine in ␣2A-AR-null (␣2A-AR ؊/؊ ) mice. Moreover, we observe that moxonidine lowers blood pressure without sedation in wild-type mice, consistent with the above hypothesis regarding partial agonists. Our findings suggest that weak partial agonists can evoke response-selective pathways and might be exploited successfully to achieve ␣2A-AR pharmacotherapy where concomitant sedation is undesirable, i.e., in treatment of depression or attention deficit hyperactivity disorder, in suppression of epileptogenesis, or enhancement of cognition. Furthermore, rigorous physiological and behavioral assessment of mice heterozygous for particular receptors provides a general strategy for elucidation of pathways that might be selectively activated by partial agonists, thus achieving response-specific therapy.

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Section: Discussionmentioning

confidence: 99%

Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Tan

Wilson

MacMillan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…The apparent dissociation between steroidogenesis and cAMP formation can also be explained by the spare receptor concept (31,32). However, studies with several analogs of ACTH (22,33) as well as analysis of the inhibition of the two responses by inhibitory analogs (17,34) (38).…”

Section: Resultsmentioning

confidence: 99%

Characterization of corticotropin receptors on adrenocortical cells.

Buckley¹,

Ramachandran²

1981

Proc. Natl. Acad. Sci. U.S.A.

139

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The binding ofcorticotropin (ACTH) to receptors on isolated rat adrenocortical cells was investigated with the aid of [['25I]ITyro, Phe2, Nle4]ACTH-(1-38) (1'I-ACTH analog) which retained full biological potency and had a specific radioactivity of 1800 ± 75 Ci/mmol. Binding was highly specific to adrenocortical cells, and the radioactive peptide was displaced by low concentrations ofACTH but not by other basic peptides. Bind Despite numerous attempts to investigate corticotropin (ACTH) receptors by direct binding methods, detection and characterization ofthe physiologically relevant receptors for the hormone has proved to be a formidable task. The two major difficulties encountered in binding studies with ACTH are the extraordinary propensity of the hormone to bind to inert materials and nonreceptor components of the target tissue, and the low biological potencies of the radiolabeled ACTH preparations generally used in binding studies (1-4).The "2I-labeled ACTH (125I-ACTH) preparations used by Lefkowitz et aL (1) and Ontjes et aL (3) had biological activities of32 and 15 units/mg, respectively, compared to a value of200 units/mg for unmodified ACTH reported by Rae and Schimmer (5), as measured by the stimulation of adenylate cyclase in adrenocortical cell membrane fractions. McIlhinney and Schulster (6, 7) prepared '"I-ACTH having 50% of the steroidogenic activity of the native hormone by the lactoperoxidase method.Structure-function studies (5,8,9) have shown that the loss of biological potency of ACTH results from the introduction of a bulky iodine atom into the tyrosine residue in position 2 and the oxidation of the methionine residue in position 4. We recently circumvented these difficulties by synthesizing an analog of the hormone in which the tyrosine in position 2 is replaced by phenylalanine and the methionine in position 4 is replaced by norleucine (10). This peptide, referred to hereafter as ACTH analog, was shown to be equipotent with ACTH in stimulating steroidogenesis in adrenocortical cells. We have also shown that iodination of the ACTH analog and purification by reversephase high-pressure liquid chromatography (HPLC) yields 125I-ACTH analog with the theoretically attainable specific radioactivity and full biological potency (11). By the use of this radioligand we have succeeded in identifying the specific receptors for the hormone on rat adrenocortical cells. MATERIALS AND METHODS125I-ACTH Analog. [Phe2, Nle4]ACTH-(1-38) was synthesized by the solid-phase method and purified as described (10).[[251I]ITyr23, Phe2, Nle4]ACTH-(1-38), the 125I-ACTH analog, was prepared by the chloramine-T method and separated from free iodide by gel filtration on Sephadex LH-20 as described (11). It was stored at 4°C and freshly purified by reverse-phase HPLC for each experiment (11). The HPLC solvents were removed by lyophilization to 1/10th the original volume and the labeled peptide was diluted with medium 199 (GIBCO) containing 0.5% bovine serum albumin purified as described (12), and 0.01% bacitracin (A...

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“…In the middle frame, there is a barely noticeable trace of inhibition; in the lower frame, the inhibitory effect of edrophonium on the carbachol-potential is well marked. We are dealing here with an example of competitive interference between two depolarizing drugs, of the kind described in detail by Castillo and Katz (1957c;see also Ariens, 1954;Stephenson, 1956). Finally, the observations were repeated after the preparation had been treated for about 30 min.…”

Section: Resultsmentioning

confidence: 99%

“…The reduction of a carbachol depolarization by a large pulse of edrophonium can be explained on the asumption that both drugs combine with receptor molecules, but that the edrophonium receptor complex has less " depolarizing efficacy " (see Stephenson, 1956) than the carbachol receptor compound.…”

Section: Discussionmentioning

confidence: 99%

The Interaction Between Edrophonium (Tensilon) and Acetylcholine at the Motor End‐plate

Katz

Thesleff

1957

British Journal of Pharmacology and Chemotherapy

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The effect of edrophonium (3-hydroxy-phenyl-dimethylethylammonium chloride) on the motor end-plate and its interaction with acetylcholine and carbachol has been investigated. Use was made of intracellular recording of membrane potential and of ionophoretic micro-application of drugs from single and twin-pipettes.Small doses of edrophonium potentiate the depolarizing effect of acetylcholine, but not that of carbachol. This action can be observed with doses of edrophonium which have no depolarizing effect by themselves. Large doses of edrophonium have some depolarizing action and, at the same time, inhibit depolarizations produced by carbachol. After treatment with neostigmine, edrophonium fails to potentiate the acetylcholine response. The observations are in agreement with the view that the principal action of edrophonium on the neuromuscular junction is that of a potent and rapidly acting anticholinesterase.The effects of anticholinesterases on muscle are usually tested under conditions in which the inhibitor/enzyme reaction has approached or reached equilibrium. In recent experiments (Castillo and Katz, 1957c), a different method was used, brief localized doses of the drug being applied to an end-plate with the help of an ionophoretic micro-technique. Under these conditions, the observed potency of a drug depends on the kinetics, rather than the equilibrium constant, of the reaction. In such experiments it was found that substances like neostigmine, which are strong but slowly acting enzyme inhibitors, produced no potentiation of the acetylcholine response, while less powerful but more rapidly acting esterase inhibitors (choline, decamethonium) caused a marked increase in the acetylcholine effect. Similar experiments will be described in which edrophonium (3-hydroxy-phenyl-dimethylethylammonium chloride) was allowed to interact with acetylcholine (ACh), by applying the substances from micropipettes placed at close range to an end-plate of the frog's sartorius muscle. The membrane potential of the muscle fibre was recorded with an intracellular electrode inserted within a few hundred microns of the point of drug action.The effect of edrophonium on neuromuscular transmission in the frog has previously been studied by Nastuk and Alexander (1954), who concluded that the anticurare action of this substance and the modifications which it produced in the shape of the electric end-plate response could be attributed to its anti-esterase activity (see also Smith, Cohen, Pelikan, and Unna, 1952). The present experiments confirm this view and provide additional evidence for the high speed at which the reaction between edrophonium and ACh-esterase proceeds. METHOD The technique has been described in detail in previous papers (Castillo and Katz, 1955, 1957a, c; see also Katz and Thesleff, 1957). The experiments were made on isolated sartorius muscles of R. temporaria at about 200 C. The preparations were mounted in a bath of Ringer solution which contained the electrodes for the recording of membrane potentials and for the...

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A Modification of Receptor Theory

Cited by 799 publications

References 14 publications

Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Characterization of corticotropin receptors on adrenocortical cells.

The Interaction Between Edrophonium (Tensilon) and Acetylcholine at the Motor End‐plate

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A Modification of Receptor Theory

Cited by 799 publications

References 14 publications

Heterozygous α 2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Heterozygous α 2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Characterization of corticotropin receptors on adrenocortical cells.

The Interaction Between Edrophonium (Tensilon) and Acetylcholine at the Motor End‐plate

Contact Info

Product

Resources

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Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

Heterozygous α _2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists