Page 54 - Basic _ Clinical Pharmacology ( PDFDrive )

40 SECTION I Basic Principles

endogenous opioid and dopamine receptors, respectively). This Gouaux E, MacKinnon R: Principles of selective ion transport in channels and
approach is evolving toward understanding the structural details pumps. Science 2005;310:1461.
of how chemically similar agents differ in binding to receptors. For Homan KT, Tesmer JJ: Structural insights into G protein-coupled receptor kinase
function. Curr Opin Cell Biol 2014;27:25.
example, X-ray crystallography of β and β adrenoceptors shows Huang Y et al: Molecular basis for multimerization in the activation of the epider-
1
2
that their orthosteric binding sites are identical; drugs discrimi- mal growth factor receptor. Elife 2016;5:e14107.
nate between subtypes based on differences in traversing a diver- Kang DS, Tian X, Benovic JL: Role of β-arrestins and arrestin domain-containing
gent “vestibule” to access the orthosteric site. Many GPCRs have proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol
2014;27:63.
such passages, revealing a new basis for improving the selectivity Kenakin T, Williams M: Defining and characterizing drug/compound function.
of GPCR-targeted drugs. Biochem Pharmacol 2014;87:40.
Thus, the propensity of drugs to bind to different classes of Kho C, Lee A, Hajjar RJ: Altered sarcoplasmic reticulum calcium cycling: Targets
receptor sites is not only a potentially vexing problem in treating for heart failure therapy. Nat Rev Cardiol 2012;9:717.
patients, but it also presents a continuing challenge to pharmacol- Kobilka BK: Structural insights into adrenergic receptor function and pharmacol-
ogy and an opportunity for developing new and more useful drugs. ogy. Trends Pharmacol Sci 2011;32:213.
Liu N et al: microRNA-206 promotes skeletal muscle regeneration and delays
progression of Duchenne muscular dystrophy in mice. J Clin Invest
REFERENCES 2012;122:2054.
Brodlie M et al: Targeted therapies to improve CFTR function in cystic fibrosis. Olson EN: MicroRNAs as therapeutic targets and biomarkers of cardiovascular
Genome Med 2015;7:101. disease. Sci Transl Med 2014;6:239ps3.
Catterall WA, Swanson TM: Structural basis for pharmacology of voltage-gated Park HW, Tantisira KG, Weiss ST: Pharmacogenomics in asthma therapy: Where
sodium and calcium channels. Mol Pharm 2015;88:141. are we and where do we go? Annu Rev Pharmacol Toxicol 2015;55:129.
Christopoulos A: Advances in G protein-coupled receptor allostery: From function Quon BS, Rowe SM: New and emerging targeted therapies for cystic fibrosis.
to structure. Mol Pharmacol 2014;86:463. Br Med J 2016;352:i859.
Dar AC, Shokat KM: The evolution of protein kinase inhibitors from antagonists Rosell R, Bivona TG, Karachaliou N: Genetics and biomarkers in personalisation
to agonists of cellular signaling. Ann Rev Biochem 2011;80:7069. of lung cancer treatment. Lancet 2013;382:720.
Davies MA, Samuels Y: Analysis of the genome to personalize therapy for mela- Sprang SR: Activation of G proteins by GTP and the mechanism of Gα-catalyzed
noma. Oncogene 2010;29:5545. GTP hydrolysis. Biopolymers 2016;105:449.
Di Fiore PP, von Zastrow M: Endocytosis, signaling, and beyond. Cold Spring Thorner J et al: Signal transduction: From the atomic age to the post-genomic era.
Harb Perspect Biol 2014;6:a016865. Cold Spring Harb Perspect Biol 2014;6:a022913.
Esseltine JL, Scott JD: AKAP signaling complexes: Pointing towards the next Wisler JW et al: Recent developments in biased agonism. Curr Opin Cell Biol
generation of therapeutic targets? Trends Pharmacol Sci 2013;34:648. 2014;27:18.

C ASE STUD Y ANSWER

Propranolol, a β-adrenoceptor antagonist, is a useful antihy- a more highly selective adrenoceptor antagonist drug (such
pertensive agent because it reduces cardiac output and prob- as metoprolol) that binds preferentially to the β 1 subtype,
ably vascular resistance as well. However, it also prevents which is a major β adrenoceptor in the heart, and has a
β-adrenoceptor–induced bronchodilation and therefore may lower affinity (ie, higher K ) for binding the β subtype that
d
2
precipitate bronchoconstriction in susceptible individuals. mediates bronchodilation. Selection of the most appropriate
Calcium channel blockers such as verapamil also reduce drug or drug group for one condition requires awareness
blood pressure but, because they act on a different target, of the other conditions a patient may have and the receptor
rarely cause bronchoconstriction or prevent bronchodila- selectivity of the drug groups available.
tion. An alternative approach in this patient would be to use