1521-0081/70/3/549–620$35.00 https://doi.org/10.1124/pr.117.015305 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:549–620, July 2018 Copyright © 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: JEFFREY M. WITKIN Trace Amines and Their Receptors Raul R. Gainetdinov, Marius C. Hoener, and Mark D. Berry Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia (R.R.G.); Skolkovo Institute of Science and Technology (Skoltech), Moscow, Russia (R.R.G.); Neuroscience, Ophthalmology, and Rare Diseases Discovery and Translational Area, pRED, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (M.C.H.); and Department of Biochemistry, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada (M.D.B.) Abstract. ....................................................................................551 I. Introduction. ..............................................................................551 II. Vertebrate Trace Amines . ..................................................................555 A. b-Phenylethylamine, p-Tyramine, and Related Compounds ...............................555 1. Synthesis ............................................................................555 a. Regulation of Aromatic L-Amino Acid Decarboxylase ...............................555 b. Other Sources of b-Phenylethylamine, p-Tyramine, and Related Compounds .......560 i. Microbiota-Derived Trace Amines...............................................560 ii. Food-Derived Trace Amines ....................................................561 Downloaded from 2. Degradation. ........................................................................561 3. Storage and Passage across Membranes ..............................................561 4. Cellular Effects ......................................................................562 a. Indirect Sympathomimetic Responses . ..........................................562 b. b-Phenylethylamine. ............................................................562 by guest on September 26, 2021 c. p-Tyramine .......................................................................564 d. Tryptamine .......................................................................564 e. Octopamine .......................................................................565 5. b-Phenylethylamine, p-Tyramine, and Tryptamine in Human Disorders . .............565 B. Isoamylamine . ........................................................................566 C. Trimethylamine . ........................................................................566 D. O-Methyl and N-Methyl Derivatives .....................................................568 E. 3-Iodothyronamine.......................................................................568 1. Cardiovascular Effects................................................................569 2. Metabolic Effects . ..................................................................569 3. Thermoregulation . ..................................................................569 4. Other Effects. ........................................................................570 F. Polyamines ..............................................................................570 G. Putative Other Trace Amines ............................................................571 III. Invertebrate Trace Amines ..................................................................571 A. Synthesis and Degradation . ............................................................571 B. Storage and Release . ..................................................................571 C. Octopamine Receptors . ..................................................................572 D. Tyramine Receptors . ..................................................................572 E. Physiologic Responses . ..................................................................572 1. Octopamine . ........................................................................572 2. Tyramine ............................................................................573 IV. Trace Amine–Associated Receptors ..........................................................573 Address correspondence to: Raul R. Gainetdinov, Institute of Translational Biomedicine, St. Petersburg State University, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia. E-mail: [email protected] This work was supported by the Russian Science Foundation [Grant 14-50-00069 (to R.R.G.)] and the Research and Development Corporation of Newfoundland and Labrador and Memorial University of Newfoundland (to M.D.B.). R.R.G., M.C.H., and M.D.B. contributed equally to this work. https://doi.org/10.1124/pr.117.015305. 549 550 Gainetdinov et al. A. Evolution of Trace Amine–Associated Receptors ..........................................577 B. Trace Amine–Associated Receptor 1......................................................578 1. Pharmacology of Trace Amine–Associated Receptor 1 . ...............................584 a. Trace Amine–Associated Receptor 1 Gene Conservation. .........................584 b. Expression of Trace Amine–Associated Receptor 1 . ...............................584 c. Trace Amine–Associated Receptor 1 Ligands. .....................................588 i. Development of Selective Agonists and Partial Agonists .........................589 ii. Development of N-(3-Ethoxyphenyl)-4-(1-Pyrrolidinyl)-3-(Trifluoromethyl) Benzamide, the First Selective Antagonist .........................................589 d. Signal Transduction and Molecular Interactions ...................................590 i. Adenylyl Cyclase . ............................................................590 ii. G Protein–Coupled Inwardly Rectifying Potassium Channels . ...................590 iii. Heterodimerization with the D2-Like Dopamine Receptor.......................590 iv. b-Arrestin 2 and Biased Signaling..............................................592 v. Other Signaling Cascades ......................................................592 2. Central Nervous System Effects ......................................................592 a. Cellular Effects . ..................................................................592 i. Dopaminergic Systems . ......................................................592 ii. Serotonergic Systems ...........................................................594 iii. Glutamatergic Systems . ......................................................594 b. Behavior . ........................................................................595 i. Schizophrenia and Bipolar Disorder . ..........................................595 ii. Cognitive Effects . ............................................................595 iii. Depression . ..................................................................595 iv. Sleep, Wake, and Narcolepsy . ................................................596 v. Addiction and Compulsive Behaviors . ..........................................596 vi. Feeding Behavior . ............................................................597 3. Effects in the Periphery . ............................................................598 a. Diabetes and Obesity . ............................................................598 b. Immunomodulatory Effects . ......................................................598 c. Cancer . ........................................................................599 d. Pregnancy ........................................................................599 C. Other Tetrapod Trace Amine–Associated Receptors . .....................................599 1. Trace Amine–Associated Receptor 2 . ................................................599 2. Trace Amine–Associated Receptor 3 . ................................................600 3. Trace Amine–Associated Receptor 4 . ................................................600 4. Trace Amine–Associated Receptor 5 . ................................................600 5. Trace Amine–Associated Receptor 6 . ................................................601 6. Trace Amine–Associated Receptor 7 . ................................................601 7. Trace Amine–Associated Receptor 8 . ................................................601 8. Trace Amine–Associated Receptor 9 . ................................................602 ABBREVIATIONS: 3-MT, 3-methoxytyramine; 3IT, 3-iodothyronamine; 5-HT, 5-hydroxytryptamine; AADC, aromatic L-amino acid decarboxylase; AKT, protein kinase B; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AOC3, amine oxidase, copper containing 3; ASIC, acid-sensing ion channel; COMT, catechol-O-methyltransferase; CPP, conditioned place preference; D1R, D1-like dopamine receptor; D2R, D2-like dopamine receptor; DAT, dopamine transporter; DMT, N,N-dimethyltryptamine; DRL, differential reinforcement of low response rate; DRN, dorsal raphe nuclei; EAAT-2, excitatory amino acid transporter 2; EPPTB, N-(3-ethoxyphenyl)-4-(1- pyrrolidinyl)-3-(trifluoromethyl)benzamide (also known as RO5212773); FMO3, flavin monooxygenase 3; GLP-1, glucagon-like peptide 1; GPCR, G protein–coupled receptor; GSK3b, glycogen synthase kinase; HEK-293, human embryonic kidney 293; IUPHAR, International Union of Basic and Clinical Pharmacology; KO, knockout; L-687,414, (3S,4S)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one; MAO, monoamine oxidase; MDMA, 3,4-methylenedioxymethamphetamine;