Terry Kenakin - Academia.edu (original) (raw)

Papers by Terry Kenakin

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2022

Abbreviations: CK, casein kinase; CRIP1a, cannabinoid receptor interacting protein 1a; DERET, dif... more Abbreviations: CK, casein kinase; CRIP1a, cannabinoid receptor interacting protein 1a; DERET, diffusion-enhanced resonance energy transfer; ebBRET, enhanced bystander BRET; ERNEST, European Research NEtwork on Signal Transduction; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRK, GPCR kinase; K A , equilibrium dissociation constant of agonist-receptor complex; k off , ligand dissociation rate; k on , ligand association rate; NC-IUPHAR, Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology; PH, pleckstrin homology domain; RAMP, receptor activity-modulating protein; RGS, regulator of G protein signalling; RH, RGS homology domain; τ, coupling efficiency between the agonist/receptor complex and its downstream signalling partners.

F1000 biology reports, Nov 26, 2009

Seven-transmembrane receptors are commonly coupled to multiple signaling pathways in cells. The s... more Seven-transmembrane receptors are commonly coupled to multiple signaling pathways in cells. The simple model describing agonists for these receptors as producing a common active state to induce uniform activation of the pathways linked to the receptor has been shown to be untenable in light of a large body of data that suggest that some agonists produce activation of some but not all available pathways. These agonists are referred to as 'biased' in that they select which signaling pathways become activated upon binding to the receptor. The data to support this mechanism as well as ideas on the possible therapeutic application of this effect will be discussed.

Nature Reviews Drug Discovery, May 17, 2013

BMC Clinical Pharmacology, Aug 13, 2012

The discovery that not all agonists uniformly activate cellular signaling pathways (biased signal... more The discovery that not all agonists uniformly activate cellular signaling pathways (biased signaling) has greatly changed the drug discovery process for agonists and the strategy for treatment of disease with agonists. Technological advances have enabled complex receptor behaviors to be viewed independently and through these assays, the bias for an agonist can be quantified. It is predicted that therapeutic phenotypes will be linked, through translational studies, to quantified scales of bias to guide medicinal chemists in the drug discovery process.

SUMMARYThe NTSR1 neurotensin receptor (NTSR1) is a G protein coupled receptor (GPCR) found in the... more SUMMARYThe NTSR1 neurotensin receptor (NTSR1) is a G protein coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-Arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and Go with and without the brain penetrant small molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gαsubunit selective and positive allosteric modulation and agonism for β-Arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modula...

The mass action equation is the building block from which all models of drug–receptor interaction... more The mass action equation is the building block from which all models of drug–receptor interaction are built. In the simplest case, the equation predicts a sigmoidal relationship between the amount of drug–receptor complex and the logarithm of the concentration of drug. The form of this function is also the same as most dose–response relationships in pharmacology (such as enzyme inhibition and the protein binding of drugs) but the potency term in dose–response relationships very often differs in meaning from the similar term in the simple mass action relationship. This is because (i) most pharmacological systems are collections of mass action reactions in series and/or in parallel and (ii) the important assumptions in the mass action reaction are violated in complex pharmacological systems. In some systems, the affinity of the receptor R for some ligand A is modified by interaction of the receptor with the allosteric ligand B and concomitantly the affinity of the receptor for ligand ...

This article has not been copyedited and formatted. The final version may differ from this version.

Role of the N-terminal region in G-protein coupled receptor functions: negative

Pharmacological Reviews, 2019

ACS Pharmacology & Translational Science, 2019

The unique ways in which pharmacological data compares to mathematical models are described. Exam... more The unique ways in which pharmacological data compares to mathematical models are described. Examples show that insights into agonist action (prediction of agonism in vivo) and antagonist mechanism of action (orthosteric vs allosteric) can be gained that assist in the candidate selection process for new drugs in drug discovery and development efforts. In addition, the impact of component processes on complex physiological systems can be delineated, such as the effects of the hepatic system on whole body clearance in pharmacokinetics and prediction of drug-drug interactions. Finally, models are instrumental in the procurement of universal drug parameters that can be used in medicinal chemistry-based structureactivity relationships. The revitalization of these ideas under the banner of "Analytical Pharmacology" may serve to re-emphasize these concepts over qualitative description and lead to a better foundation for drug discovery.

ACS chemical neuroscience, Jan 6, 2018

Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB... more Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB1 negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB1 allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB1 agonist CP55,940 stimulated calcium mobilization and [35S]GTP-γ-S binding. Similar to 1, most compounds showed positive cooperativity by increasing [3H]CP55,940 binding, consistent with the positive allosteric modulator (PAM)-antagonist mechanism. Interestingly, these compounds exhibited differences in ability to increase specific binding of [3H]CP55,940 and decrease binding of the antagonist [3H]SR141716. In s...

Molecular pharmacology, 2018

This paper discusses the process of determining the activity of candidate molecules targeting Gq-... more This paper discusses the process of determining the activity of candidate molecules targeting Gq-protein activation through G-protein-coupled receptors for possible therapeutic application with two functional assays; calcium release and inositol phosphate metabolism [inositol monophosphate (IP1)]. While both are suitable for detecting ligand activity (screening), differences are seen when these assays are used to quantitatively measure ligand parameters for therapeutic activity. Specifically, responses for Gq-related pathways present different and dissimulating patterns depending on the functional assay used to assess them. To investigate the impact of functional assays on the accuracy of compound pharmacological profiles, five exemplar molecules [partial agonist, antagonist, inverse agonist, positive allosteric modulator (PAM) agonist, and positive -PAM] targeting either muscarinic M1 or ghrelin receptors were tested using two functional assays (calcium release and IP1) and the res...

Molecular pharmacology, Jan 18, 2018

The question of whether signaling bias is a viable discovery strategy for drug therapy is discuss... more The question of whether signaling bias is a viable discovery strategy for drug therapy is discussed as a value proposition. On the positive side, bias if easily identified and quantified in simple in vitro functional assays with little resource expenditure. However, there are valid pharmacological reasons why these in vitro bias numbers may not accurately translate to in vivo therapeutic systems making the expectation of direct correspondence of in vitro bias to in vivo systems a problematic process. Presently, in vitro bias is used simply as a means to identify unique molecules to be advanced to more complex therapeutic assays but from this standpoint alone, the value proposition lies far to the positive. However, pharmacological attention needs to be given to the translational gap to reduce inevitable and costly attrition in biased molecule progression.

ACS Chemical Neuroscience, 2016

The modification of ongoing chemical signaling in the brain through allosteric modification of se... more The modification of ongoing chemical signaling in the brain through allosteric modification of seven transmembrane receptors offers a wealth of diverse beneficial outcomes in drug therapy. Specifically, biased agonism can emphasize beneficial signals and de-emphasize harmful signals thus increasing the effectiveness of agonists and opening up new vistas for previously precluded drug targets. In addition, the modification of natural agonism through positive and negative allostery can provide useful rejuvenation of failing systems.

Molecular Pharmacology, 2017

An index of agonism is described that can be used to quantify agonist receptor selectivity, bias,... more An index of agonism is described that can be used to quantify agonist receptor selectivity, bias, cell-based agonism, and the effects of receptor mutation on signaling. The parameter is derived from agonist concentration-response curves and comprises the maximal response to the agonist (max) and the EC 50 in the form of Dlog(max/EC 50 ). This parameter is derived from equations describing agonists as positive allosteric facilitators of receptor-signaling protein interaction. A similar index is also derived to quantify the potentiating effects of positive allosteric modulators, which can be used to quantify in situ positive allosteric modulator activity in vivo. These indices lend themselves to statistical analysis and are system-independent in that the effects of the system processing of agonist response and differences in assay sensitivity and receptor expression are cancelled. The various applications of the Dlog(max/EC 50 ) scale are described for each pharmacologic application.

Medicinal research reviews, May 23, 2016

The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many ... more The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details...

Molecular and Cellular Endocrinology, 2016

Pharmacoperones rescue misrouted mutants of the vasopressin receptor type 2 (V2R) and enable them... more Pharmacoperones rescue misrouted mutants of the vasopressin receptor type 2 (V2R) and enable them to traffic to the correct biological locus where they function. Previously, a library of nearly 645,000 structures was interrogated with a high throughput screen; pharmacoperones were identified for V2R mutants with a view toward correcting the underlying mutational defects in nephrogenic diabetes insipidus. In the present study, an orthologous assay was used to evaluate hits from the earlier study. We found no consistent relation between antagonism or agonism and pharmacoperone activity. Active pharmacoperones were identified which had minimal antagonistic activity. This increases the therapeutic reach of these drugs, since virtually all pharmacoperone drugs reported to date were selected from peptidomimetic antagonists. Such mixed-activity drugs have a complex pharmacology limiting their therapeutic utility and requiring their removal prior to stimulation of the receptor with agonist.

A Pharmacology Primer, 2014

This chapter puts the role of pharmacology into the perspective of modern methods employed in the... more This chapter puts the role of pharmacology into the perspective of modern methods employed in the drug discovery and development process. Target-based vs system-based strategies are contrasted as well as the role of screening and libraries. Finally, discussion of the clinical testing of new drugs is highlighted.

Handbook of Experimental Pharmacology, 2000

The use of general descriptive names, registered names, etc. in this publication does not imply, ... more The use of general descriptive names, registered names, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Coverdesign: design & production GmbH, Heidelberg Typesetting: Best-set Typesetter Ud., Hong Kong SPIN: 10650831 27/3020-54321 0-printed on acid-free paper VI Preface depicts the new technological approaches to the study of receptors and their function. Sixty three years after Clark's volume, technology has revolutionized pharmacology. However, while the means to answer the questions have completely changed, the questions remain the same.