Pharmac. Ther. Vol. 47, pp. 73-104, 1990 0163-7258/90 $0.00 + 0.50 Printed in Great Britain. All rights reserved © 1990 Pergamon Press pie Free-Standing Review HISTAMINE RECEPTORS: SUBCLASSES AND SPECIFIC LIGANDS E. E. J. HAAKSMA, R. LEURSand H. TIMMERMAN Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands Abstract--In this review the three main types of histamine receptors are discussed together with their specific ligands. For the classical H~-receptors much emphasis is put on the mechanism by which the receptor is stimulated. For the H t - and H2-receptor the review includes information on the several models available for establishing agonistic or antagonistic activity. In the section on the H3-receptor the ligands are discussed as well as the possible physiological role of this receptor. In the final paragraphs some less well defined activities are presented. CONTENTS I. Introduction 74 2. The Histamine H~-Receptor 74 2.1. Selective HL-ligands 74 2.1.1. Agonists 74 2.1.2. Antagonists 75 2.1.3. Stereoselectivity, irreversible antagonists 77 2.2. Receptor mechanism, signal transfer 77 2.2.1. Ca 2+ mobilization 77 2.2.2. Phosphatidylinositol turnover 77 2.2.3. G-protein regulation 78 2.2.4. Second messenger production 79 2.2.5. Ca 2÷ influx 80 2.3. Pharmacological models for the H~-receptor 80 2.3.1. In vitro radioligand binding assay 80 2.3.2. Autoradiographic labelling of Hrreceptor 82 2.3.3. Measurement of production of second messengers 82 2.3.4. In vitro tissue preparation; functionality tests 83 2.3.5. In vivo test systems for the H~-receptor 83 2.4. Species and tissue differences of the Ht-receptor system 84 3. The Histamine H2-Receptor 85 3.1. Selective H2-1igands 85 3.1.1. Agonists 85 3.1.2. Antagonists 86 3.1.3. Stereoselectivity 87 3.2. Receptor mechanism, signal transfer 88 3.3. Pharmacological models for the Ha-receptor 89 3.3.1. In vitro radioligand binding assay 89 3.3.2. In vitro tissue preparations; functionality tests 90 3.3.3. In vivo test systems for the H2-receptor 91 3.4. Histamine H2-receptor subtypes 92 3.5. Histamine H2-receptor desensitization 92 4. The Histamine H3-Receptor 93 4. l. Introduction 93 4.2. The presynaptic (H3) histamine receptor 93 4.3. Some characteristics of the H3-receptor 94 4.4. Selective ligands for the H3-receptors 95 4.5. Localization of H3-receptors 96 4.6. Physiological role of the H3-receptor 96 5. Less Well Defined Histamine Receptors 98 5.1. Histamine receptors on immuno-active cells 98 5.2. Histamine receptors and estrogen activity 98 References 99 73