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Terry Kenakin

Publications and source records attributed to Terry Kenakin.

At least 19 recordsLinked to original sources
PubMed2006

Determining the potency and molecular mechanism of action of insurmountable antagonists.

Insurmountable antagonism (maximal response to the agonist depressed) can result from a temporal inequilibrium involving a slow offset orthosteric antagonist or be the result of an allosteric modulation of the receptor. The former mechanism is operative when the antagonist, agonist, and receptors cannot come to proper equilibrium during the time allotted for collection of agonist response (hemi-equilibrium conditions). Allosteric effects (changes in the conformation of the receptor through binding of the allosteric modulator to a separate site) can preclude the agonist-induced production of response, leading to depression of maximal responses. In these cases, the effects on receptor affinity can be observed as well. The first premise of this article is that system-independent estimates of insurmountable antagonist potency can be made with no prior knowledge of molecular mechanism through the use of pA(2) (-log molar concentration of antagonist producing a 2-fold shift of the concentration response curve) measurements The relationship between the pA(2) and antagonist pK(B) (-log equilibrium dissociation constant of the antagonist-receptor complex) is described; the former is an extremely close approximation of the latter in most cases. The second premise is that specially designed experiments are required to differentiate orthosteric versus allosteric mechanisms; simply fitting of data to orthosteric or allosteric theoretical models can lead to ambiguous results. A strategy to determine whether the observed antagonism is orthosteric (agonist and antagonist competing for the same binding site on the receptor) or allosteric in nature is described that involves the detection of the hallmarks of allosteric response, namely saturation and probe dependence of effect.

Allosteric Regulation↗
PubMed2006

GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist.

1. N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity. 2. At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration-effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9 +/- 0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 4. In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb = 9.2 +/- 0.2; slope = 1). 4. GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 microM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 approximately 7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 microM) did not displace U-46619 E/[A] curves indicating an affinity of < 5.0 for rabbit and guinea-pig prostanoid TP receptors. 5. In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was < 5.0. 6. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi = 7.0 +/- 0.2 (n = 10) and 6.8 (n = 2), respectively). Affinity for all other human prostanoid receptors was < 5.3. 7. GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.

Animals↗
PubMed2006

Data-driven analysis in drug discovery.

In the process of drug discovery for new chemical entities, application of appropriate pharmacological models often is not possible because the molecular mechanism of the compound is not yet elucidated. Therefore, a data-driven approach using generic tools designed to quantify characteristic patterns of concentration-response curves is required. This article outlines the options available for quantifying agonist and antagonist activity. Specifically, for agonists, the use of the Operational model for the determination of functional effects (equimolar potency ratios for full agonists, calculation of relative efficacy) is described. For antagonists, the measurement of pKB (-log of the equilibrium dissociation constant of the antagonist-receptor complex) for orthosteric antagonists that do not alter basal response (simple competitive antagonists), increase basal response (partial agonists), and decrease basal response (in constitutively active systems; inverse agonists) is discussed. In addition, this article considers methods to discern orthosteric receptor antagonism from allosteric antagonism whereby the agonist and antagonist bind to separate sites and interact through a conformational change in the receptor. Methods for the measurement of the pKB for allosteric modulators as well as co-operativity constants for these modulators is described.

Allosteric Regulation↗
PubMed2005

The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.

4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pK(B) = 8.6 +/- 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidin-4-yl}methanone O-ethyloxime (Sch-C; SCH 351125), 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R)-2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinyl]carbonyl}pyrimidine (Sch-D; SCH 417,690), 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenyl-propyl)cyclohexanecarboxamide (UK-427,857), and N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK779) blocked the binding of both chemokines (125)I-MIP-1alpha (also known as (125)I-CCL3, (125)I-LD78) and (125)I-RANTES ((125)I-CCL5), 873140 was an ineffectual antagonist of (125)I-RANTES (regulated on activation normal T cell expressed and secreted) binding (but did block binding of (125)I-MIP-1alpha). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 (RANTES) (as did the other antagonists), indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe-dependent, consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of <0.004 h(-) (1) (t(1/2) > 136 h). Coadministration studies of 873140 with the four other allosteric antagonists yielded data that are consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. Although these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor, as indicated by their differential effects on the binding of (125)I-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.

Animals↗
PubMed2005

New concepts in drug discovery: collateral efficacy and permissive antagonism.

New perspectives on the complexity of G-protein-coupled receptor (GPCR) signalling and the increased resolution of existing tools for studying GPCR behaviour has led to the conception of new hypotheses that affect the discovery of drugs acting at GPCRs. Taking into consideration the novel concepts of collateral efficacy and permissive antagonism in the search for synthetic agonists and antagonists, respectively, will be essential in the search for drugs with unique therapeutic profiles. Here, the design of drugs against HIV is used as an example of how these concepts might be taken into consideration for GPCR-targeted drugs in general.

Allosteric Regulation↗
PubMed2004

Principles: receptor theory in pharmacology.

Pharmacological receptor theory is discussed with special reference to advances made during the past 25 years. Thus, the operational model has supplanted analysis of drug-receptor interaction in functional systems whereas the extended ternary complex model is used routinely to simulate quantitatively G-protein-coupled receptor (GPCR) behavior. Six new behaviors for GPCRs, centered on spontaneous production of receptor active states, ligand-selective receptor active states, oligomerization with other proteins (receptor and non-receptor) and allosteric mechanisms, have been characterized and each holds the potential for new drug discovery for therapeutic benefit.

Humans↗
PubMed2004

G-protein coupled receptors as allosteric machines.

Allosterism, whereby small molecule ligands produce global changes in the conformations of receptors, is a powerful mechanism for drug effect. This is illustrated by the recent data describing CCR5 antagonists as blockers of HIV infection. Allosteric effects are described in terms of a change in the tertiary conformation of the receptor. This paper outlines some unique features of allosteric antagonists as new drug entities. These include the fact that allosteric ligands have texture in antagonism (not all allosterically blocked receptors are alike), allosteric blockade is probe dependent (not all agonists and radioligands are blocked equally), and the fact that allosteric binding involves a separate site on the receptor may have relevance to duration of effect and selectivity. Dissociation between receptor function and binding also can be encountered with allosteric ligands.

Alcuronium↗
PubMed2004

Allosteric modulators: the new generation of receptor antagonist.

Allosteric antagonists modulate the affinity and/or efficacy of agonists for receptors. Although the manner in which this modulation can occur can mimic that of simple competitive antagonists, allosteric antagonists possess unique properties that can present seemingly capricious profiles of antagonism. These unique properties also offer potentially useful patterns for therapeutic utility. This review summarizes methods to detect allosteric antagonism and some special properties of these receptor modulators.

Allosteric Regulation↗
PubMed2004

Efficacy as a vector: the relative prevalence and paucity of inverse agonism.

This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.

Animals↗
PubMed2003

Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors.

This review addresses key pharmacology and virology issues relevant in discovery and development of CCR5 antagonists as anti-HIV drugs, such as target validation, receptor internalization, allosterism, viral resistance and tropism. Recent progress in the discovery and development of CCR5 antagonists, SAR and clinical status are reviewed. Finally, modeling-based structure of CCR5 is discussed in the context of a small-molecule antagonism of the CCR5 receptor.

Animals↗
PubMed2003

Predicting therapeutic value in the lead optimization phase of drug discovery.

Recombinant and natural cellular assays for human G-protein-coupled receptors are used to optimize initial lead molecules obtained from screening. Although the activity of these molecules can be assessed on human genotype receptors, there is increasing evidence that cells impose a phenotypic selectivity to molecules in various cellular backgrounds. This opens the possibility of dissimulations between activity seen in lead optimization assays and the intended therapeutic value in humans. This review discusses the mechanisms by which cells can impose phenotypic selectivity on molecules and approaches to reduce this practical problem for drug discovery.

Animals↗
PubMed2003

International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology.

The recommendations that follow have been updated from the proposals of a Technical Subcommittee set up by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (Jenkinson DH, Barnard EA, Hoyer D, Humphrey PPA, Leff P, and Shankley NP (1995) International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. IX. Recommendations on terms and symbols in quantitative pharmacology. Pharmacol Rev 47:255-266).

Pharmaceutical Preparations↗
PubMed2002

The ligand paradox between affinity and efficacy: can you be there and not make a difference?

Efficacy is described in terms of the ligand-induced bias of receptor micro-conformations. A virtual simulation of binding of a collection of random ligands can reconcile an apparent paradox in receptor theory, namely the theoretical requirement that affinity and efficacy be related to each other and the experimental fact that medicinal chemistry often can separate structure-activity relationships for affinity and efficacy. The simulation indicates that homoscedacity in the relationship allows for a general correlation with isolated instances of non-compliance. This leads to the conclusion that if a ligand binds to the receptor it will change the receptor by its presence. Therefore, this suggests that all ligands with macro-affinity should be extensively studied for pharmacological activities other than simple G-protein activation with the potential promise of discovering new therapeutic applications for old drugs.

Ligands↗
PubMed2002

Efficacy at G-protein-coupled receptors.

At present, the drug-discovery process centres on ligands that either block or produce physiological responses. However, there are therapeutic uses for ligands that do neither of these things, but which still affect receptors in other ways. This review discusses the intimate relationship between the affinity of a ligand for its receptor, and the probability that the binding of the ligand will produce some change in the receptor, resulting in efficacy. This, in turn, argues that ligands that have affinity should be tested more broadly, for a wider range of efficacies, to detect hidden therapeutic activities.

Animals↗