pA, A NEW SCALE FOR THE MEASUREMENT OF DRUG ANTAGONISM

Schild, H. O.

doi:10.1111/j.1476-5381.1947.tb00336.x

Cited by 613 publications

(306 citation statements)

References 4 publications

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“…No assumptions about the relationship between the response and the fraction of receptors occupied has to be made when studying the blocking effectiveness of competitive inhibitors according to a null me-thod introduced by Schild (1947). The method was based on earlier suggestions by Clark and Raventos (1937), according to which the antagonisti c power of a b10cking agent was expressed as "the concentrati on of antagonist which a1tered by a selected proportion (e.g.…”

Section: General Introductionmentioning

confidence: 99%

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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Section: General Introductionmentioning

confidence: 99%

Transformation of Adrenergic Receptors in the Myocardium

1973

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“…tested for antagonist activity). Multiple agonist dosekesponse curves were obtained in the absence and in the presence of multiple concentrations of antagonist compounds for the calculation of PA, values [24].…”

Section: Bioassaysmentioning

confidence: 99%

Conversion of Enkephalin and Dermorphin into δ‐Selective Opioid Antagonists by Single‐Residue Substitution

Tancredi¹,

Salvadori

Amodeo

et al. 1994

European Journal of Biochemistry

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The properties of di-and tri-peptides containing 1,2,3,6tetrahydroisoquinoline-3-carboxylic acid (Tic) in second position suggest that the message domain of opioid peptides can be composed of only two residues [Temussi, P. A., Salvadori, S., Amodeo, P., Guerrini, R., Tomatis, R., Lazarus, L. H., Picone, D. & Tancredi, T. (1994) Biochem. Biophys. Res. Commun. 198,. As a crucial test of the possibility that the Tyr-Tic segment be a message domain in longer peptide sequences, we have inserted it in the sequences of two typical opioid peptides: [Leulenkephalin, a non-selective agonist, and dermorphin, a selective p agonist. Here we report the synthesis and biological activity of [~-Tic'] Abhreviations. (C2H3)2S0, fatty deuterated dimethylsulfoxide; DQF-COSY, double quantum filtered correlation spectroscopy; Fmoc, fluoren-9-ylmethoxycarbonyl; NOESY, nuclear Overhauser effect spectroscopy ; Pen, p,p-dimethylcysteine (penicillamine) ; ROESY, rotating frame Overhauser effect spectroscopy; Tic, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ; TOCSY, total correlation spectroscopy. MATERIALS AND METHODS Synthesis of peptidesPeptide amides were synthesized by solid-phase methods using fluoren-9-ylmethoxycarbonyl (Fmoc) in the peptide amide linker [5-(4'-Fmoc-aminomethyl-3',5'-dimethoxyphenoxy)-valeric acid] on the poly(ethy1ene glycol)/polystyrene suport (0.18 mmol/g, 0.09 mmol; Millipore. Nu-Fmoc derivatives of amino acids were used in the coupling reactions. The reactive side chains of Tyr and Ser were protected

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“…In case opiates and peptides would act on the same receptor they would be expected to be antagonized by the same antagonist and at a given concentration of an antagonist, a certain agonistic effect should be reduced to the same extent [24]. Indeed, this is observed in the hybrid cell system with naloxone as the antagonist and either Leu' -enkephalin [ 121 or morphine as agonists [ 11,25] .…”

Section: Discussionmentioning

confidence: 99%