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T Kenakin

Publications and source records attributed to T Kenakin.

11 recordsLinked to original sources
PubMed1995

Agonist-receptor efficacy. I: Mechanisms of efficacy and receptor promiscuity.

The description of drug effects on receptor proteins is based on models and equations used to describe mass-action kinetics of molecules and inert surfaces. These models provide an adequate description of drug affinity, that is, how well a molecule binds to a receptor protein, but the way in which ligands change receptor populations to impart signals to cells remains to be determined. In the first of two articles, Terry Kenakin discusses a basic question in receptor pharmacology, namely the nature of ligand efficacy.

Animals↗
PubMed1995

Agonist-receptor efficacy. II. Agonist trafficking of receptor signals.

There is evidence to suggest that receptors with seven transmembrane domains can exist in G protein-activating conformations. It is not known how many activated receptor forms exist for each receptor. Furthermore, if there are multiple forms, does the chemical structure of the agonist determine which form dominates, and therefore, which response pathway is activated? This latter scheme is referred to as agonist-receptor trafficking, and is discussed in this, the second of two articles by Terry Kenakin. One way to approach these questions is to study receptors that couple to more than one G protein and, in essence, to try to allow the G protein to indicate the receptor state.

Animals↗
PubMed1990

Drugs and receptors. An overview of the current state of knowledge.

This paper reviews the theoretical concepts and methods utilised with isolated tissues to characterise drugs and drug receptors. Specifically the impact, on the in vitro measurement of agonist affinity and relative efficacy, of the idea that receptors bind to transduction proteins in the lipid bilayer of the cell membrane is discussed. The effects of ternary complex formation of agonist-receptor equilibria raise theoretical objections to the measurement of agonist receptor equilibrium dissociation constants. Possible 'promiscuity' of receptors with respect to the G-proteins with which they can interact makes classification of receptors by agonists suspect. The use of Schild analysis for the measurement of antagonist affinity and subsequent classification of receptors is considered in the light of recent data showing that estimates calculated with this method are heterogeneous. Resultant analysis for the detection of allosteric effects is also discussed. Lastly, the impact of molecular biology on the drug and drug receptor classification process is considered, as well as the effects of pathological processes on drug action at the receptor level.

Animals↗
PubMed1989

Pharmacologic discrimination between receptor heterogeneity and allosteric interaction: resultant analysis of gallamine and pirenzepine antagonism of muscarinic responses in rat trachea.

The antagonism of muscarinic receptor-mediated contraction of rat trachea by a range of muscarinic antagonists was quantified by Schild and resultant analysis. Dose-response curves to carbachol, muscarine and oxotremorine were shifted to the right by gallamine and pirenzepine in a parallel manner with no change in maximal response ostensibly indicating simple competitive inhibition. However, Schild analysis indicated differences in the blockade and estimated pKb values with each agonist for both gallamine and pirenzepine. This suggested either that the responses to these three agonists were mediated by a heterogeneous receptor population in this tissue or that the blockade produced by gallamine and by pirenzepine was not competitive. Further Schild analysis with the muscarinic antagonists scopolamine, atropine, 4-diphenylacetoxy-N-methyl piperidine methiodide and (11 [(2-[(diethylamino)methyl]-1-piperidinyl]acetyl)-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine 6-one) with carbachol, muscarine and oxotremorine indicated simple competitive antagonism of a homogeneous population of muscarinic receptors. Therefore, the competitivity of binding of atropine, gallamine and pirenzepine with the scopolamine binding site was measured with the recently reported technique of resultant analysis. With this method the effect of various concentrations of the test antagonist on the antagonism produced by specified concentrations of the reference antagonist scopolamine was measured and the equilibrium dissociation constant of the test antagonist-receptor complex estimated. These data indicated that atropine and scopolamine bind to a common binding site on the muscarinic receptor, but that scopolamine and both gallamine and pirenzepine bind to mutually exclusive sites. This result is mine and pirenzepine are allosteric modulators of muscarinic receptors which bind at sites other than that utilized by agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1988

Are receptors promiscuous? Intrinsic efficacy as a transduction phenomenon.

The classical pharmacologic scales of agonist affinity and relative intrinsic efficacy, as utilized for drug and drug receptor classification, are examined in terms emerging concepts of receptor signal transduction. Specifically, evidence is considered that within the membrane of some cells, receptors may couple to more than one type of G-protein after agonist activation and that the relative dependence of response to different coupling proteins would make agonist efficacy a tissue dependent and not strictly a receptor dependent property. Since efficacy would depend upon the chemical nature of at least two receptor recognition domains (an extracellular domain for agonist recognition and a cytosolic domain for G-protein recognition), and agonist and antagonist affinity would depend upon only one, quantitative classification data utilizing these two scales would be divergent.

Animals↗
PubMed1982

Irreversible blockade of responses to a partial agonist acting at the histamine H1-receptor.

N,N-Diethyl-2-(1-pyridyl)-ethylamine (E-2-P) has been shown previously to behave as a simple partial agonist at the histamine H1-receptor of guinea-pig ileum. When isolated longitudinal muscle strips from this preparation were tested with E-2-P before and after blockade with 2-haloalkylamines, it was found that these agents produced an irreversible shift to the right in the dose-response curve without significant depression of the maximum response even at very high antagonist concentrations. Under these circumstances the maximum response to the partial agonist may exceed the maximum response to histamine itself since the latter shows a much diminished maximum response at a very high concentrations of antagonist. These findings are not readily explicable in terms the usual "receptor-reserve' model of the histamine receptor system in ileum. A tentative explanation is provided, involving interaction with the antagonist at more than one site.

Animals↗