.alpha.- and .beta.-Adrenoceptors: From the Gene to the Clinic. Part 1. Molecular Biology and Adrenoceptor Subclassification

Journal of Medicinal Chemistry
1995.0

Abstract

Blockade of the actions of the sympathetic neurotransmitter norepinephrine and the neurohormone epinephrine at α- and β-adrenoceptors has represented an important mechanism in drug therapy for decades, with a vast array of agonists and antagonists developed as therapeutic agents (e.g., β-adrenoceptor antagonists for hypertension, angina, and secondary prevention of acute myocardial infarction; β2-adrenoceptor agonists as bronchodilators in asthma and other bronchospastic conditions; α2-adrenoceptor agonists as well as α1-adrenoceptor antagonists for hypertension). Subtypes of each major class of adrenoceptors have been known for many years (β-adrenoceptors first subdivided in 1967, α-adrenoceptors initially subdivided in 1973), and recent identification of additional subtypes (e.g., β3-adrenoceptor for diabetes and obesity, further subdivision of α1-adrenoceptors for prostatic urethral obstruction) has stimulated increased interest in the design of subtype-selective agents. Molecular biological techniques facilitated the discovery of some subtypes (e.g., additional α1- and α2-adrenoceptor subtypes), while classical pharmacological techniques identified others (e.g., β3-adrenoceptor) and selective agents were synthesized and evaluated in humans before receptor sequencing. Subtype-selective agents often result in more efficacious drugs (e.g., α1-adrenoceptor selective prazosin for hypertension), and the recent proliferation of subtypes is likely to improve therapy. This review covers the molecular biology and classification of α- and β-adrenoceptors, including cloning and characterization of α1, α2, and β subtypes, their pharmacologic profiles, tissue distribution, and nomenclature.

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