title: Identification of the antiarrhythmic drugs amiodarone and lorcainide as potent H3 histamine receptor inverse agonists.
abstract: Use of molecular pharmacology to reprofile older drugs discovered before the advent of recombinant technologies is a fruitful method to elucidate mechanisms of drug action, expand understanding of structure-activity relationships between drugs and receptors, and in some cases, repurpose approved drugs. The H3 histamine receptor is a G-protein-coupled receptor (GPCR) primarily expressed in the central nervous system where among many things it modulates cognitive processes, nociception, feeding and drinking behavior, and sleep/wakefulness. In binding assays and functional screens of the H3 histamine receptor, the antiarrhythmic drugs lorcainide and amiodarone were identified as potent, selective antagonists/inverse agonists of human and rat H3 histamine receptors, with relatively little or no activity at over 20 other monoamine GPCRs, including H1, H2, and H4 receptors. Potent antagonism of H3 receptors was unique to amiodarone and lorcainide of 20 antiarrhythmic drugs tested, representing six pharmacological classes. These results expand the pharmacophore of H3 histamine receptor antagonist/inverse agonists and may explain, in part, the effects of lorcainide on sleep in humans.
authors.affiliation: ACADIA Pharmaceuticals Inc., San Diego, California.
authors.forename: Andria L
authors.initials: AL
authors.lastname: Del Tredici
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
mesh_terms: D000638:Amiodarone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D017442:Histamine Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D044482:Benzeneacetamides; D017442:Histamine Agonists; D010880:Piperidines; D018100:Receptors, Histamine H3; C015970:lorcainide; D000638:Amiodarone