Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts Edited by Arpad Szallasi and Susan M. Huang Printed Edition of the Special Issue Published in Pharmaceuticals www.mdpi.com/journal/pharmaceuticals Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts Special Issue Editor Arpad Szallasi Susan M. Huang MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Arpad Szallasi Susan M. Huang Baptist-MD Anderson Cancer Center AbbVie Inc. USA USA Editorial Office MDPI AG St. Alban-Anlage 66 Basel, Switzerland This edition is a reprint of the Special Issue published online in the open access journal Pharmaceuticals (ISSN 1424-8247) from 2016–2017 (available at: http://www.mdpi.com/ journal/pharmaceuticals/special_issues/old_concepts_new_thoughts). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: Author 1; Author 2. Article title. Journal Name Year, Article number, page range. First Edition 2017 ISBN 978-3-03842-638-7 (Pbk) ISBN 978-3-03842-639-4 (PDF) Articles in this volume are Open Access and distributed under the Creative Commons Attribution license (CC BY), which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book taken as a whole is © 2017 MDPI, Basel, Switzerland, distributed under the terms and conditions of the Creative Commons license CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). Table of Contents About the Special Issue Editors ................................................................................................................... v Susan Huang and Arpad Szallasi Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts Reprinted from: Pharmaceuticals 2017, 10(3), 64; doi: 10.3390/ph10030064............................................ 1 Man-Kyo Chung and James N. Campbell Use of Capsaicin to Treat Pain: Mechanistic and Therapeutic Considerations Reprinted from: Pharmaceuticals 2016, 9(4), 66; doi: 10.3390/ph9040066 ................................................ 5 Dorothy Cimino Brown Resiniferatoxin: The Evolution of the “Molecular Scalpel” for Chronic Pain Relief Reprinted from: Pharmaceuticals 2016, 9(3), 47; doi: 10.3390/ph9030047 ................................................ 25 Vincenzo Carnevale and Tibor Rohacs TRPV1: A Target for Rational Drug Design Reprinted from: Pharmaceuticals 2016, 9(3), 52; doi: 10.3390/ph9030052 ................................................ 36 Aaron D. Mickle, Andrew J. Shepherd and Durga P. Mohapatra Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies Reprinted from: Pharmaceuticals 2016, 9(4), 72; doi: 10.3390/ph9040072 ................................................ 56 Lisa M. Broad, Adrian J. Mogg, Elizabeth Eberle, Marcia Tolley, Dominic L. Li and Kelly L. Knopp TRPV3 in Drug Development Reprinted from: Pharmaceuticals 2016, 9(3), 55; doi: 10.3390/ph9030055 ................................................ 82 Michael J. Caterina and Zixuan Pang TRP Channels in Skin Biology and Pathophysiology Reprinted from: Pharmaceuticals 2016, 9(4), 77; doi: 10.3390/ph9040077 ................................................ 99 Andy D. Weyer and Sonya G. Lehto Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine Reprinted from: Pharmaceuticals 2017, 10(2), 37; doi: 10.3390/ph10020037............................................ 127 Indranil Mukhopadhyay, Abhay Kulkarni and Neelima Khairatkar-Joshi Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise? Reprinted from: Pharmaceuticals 2016, 9(4), 70; doi: 10.3390/ph9040070 ................................................ 136 Eva Millqvist TRPV1 and TRPM8 in Treatment of Chronic Cough Reprinted from: Pharmaceuticals 2016, 9(3), 45; doi: 10.3390/ph9030045 ................................................ 148 Guillaume P. Grolez and Dimitra Gkika TRPM8 Puts the Chill on Prostate Cancer Reprinted from: Pharmaceuticals 2016, 9(3), 44; doi: 10.3390/ph9030044 ................................................ 159 iii Eiichi Kumamoto and Tsugumi Fujita Differential Activation of TRP Channels in the Adult Rat Spinal Substantia Gelatinosa by Stereoisomers of Plant-Derived Chemicals Reprinted from: Pharmaceuticals 2016, 9(3), 46; doi: 10.3390/ph9030046 ................................................ 166 Nelson S. Yee Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target Reprinted from: Pharmaceuticals 2017, 10(2), 39; doi: 10.3390/ph10020039............................................ 184 Andrea Zsombok and Andrei V. Derbenev TRP Channels as Therapeutic Targets in Diabetes and Obesity Reprinted from: Pharmaceuticals 2016, 9(3), 50; doi: 10.3390/ph9030050 ................................................ 198 Shinichiro Yamamoto and Shunichi Shimizu Targeting TRPM2 in ROS-Coupled Diseases Reprinted from: Pharmaceuticals 2016, 9(3), 57; doi: 10.3390/ph9030057 ................................................ 214 Yagnesh Nagarajan, Grigori Y. Rychkov and Daniel J. Peet Modulation of TRP Channel Activity by Hydroxylation and Its Therapeutic Potential Reprinted from: Pharmaceuticals 2017, 10(2), 35; doi: 10.3390/ph10020035............................................ 231 iv About the Special Issue Editors Arpad Szallasi is a Diplomate of the American Board of Pathology. At present, he is the Medical Director of Hematopathology at Baptist Medical Center and Baptist-MD Anderson Cancer Center, Jacksonville, Florida, USA. He received his MD degree Summa cum Laude from the University Medical School of Debrecen, Hungary. He also holds a PhD degree in Pharmacology from the Karolinska Institute. In the past, he held research positions in both academia and the pharma industry. He has published over a hundred peer-reviewed papers, invited reviews and book chapters on the roles of TRP channels in health and disease. Moreover, he is the editor of four books and several thematic journal issues on TRP channels. He is an Associate Editor to Pharmaceuticals and Temperature, and he has sat on the scientific advisory board of several biotech companies with an active TRP channel research program. v pharmaceuticals Editorial Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts Susan Huang 1 and Arpad Szallasi 2,* 1 AbbVie Inc, 1 North Waukegan Road, North Chicago, IL 60064, USA; [email protected] 2 Baptist Medical Center, 800 Prudential Drive, Jacksonville, FL 32207, USA * Correspondence: [email protected] Received: 25 June 2017; Accepted: 26 June 2017; Published: 6 July 2017 2017 marks the 20th anniversary of the molecular cloning by David Julius and colleagues (1997) of the long sought-after capsaicin receptor, now known as TRPV1 (Transient Receptor Potential Vanilloid 1) [1]. This seminal discovery has opened up a “hot” new field of basic research and launched drug discovery efforts into the large family (by the latest count 28 mammalian members, 27 in humans) of TRP ion channels [2]. Indeed, it took less than a decade for the first potent, small molecule TRPV1 antagonists to enter phase 1 clinical trials [3]. Yet, despite the large amount of resources that has been invested in TRPV1 research, there are currently no TRPV1-targeted drugs in phase 3 clinical trials. In this special issue of Pharmaceuticals, we aim to capture the progress in the TRP channel field over the past twenty years, with 15 articles covering a variety of TRP channels and potential relevant disease states and applications. Fitting to the root of TRP channel discovery, Mickle and colleagues provide a comprehensive review of the nociceptive TRP ion channels, including TRPV1 [4]. TRP channel activation by specific physical-chemical stimuli, expression in the nociceptive system, and involvement in various types of pain are discussed. They argue that inhibition of TRP channels expressed on nociceptive neurons represents a viable therapeutic pain target. Small molecule modulators of TRP channels that have already progressed into clinical development for the treatment of pain are also discussed. Natural products offer a rich source of chemical diversity to identify novel drug candidates. Indeed, one in three new medicines approved by the FDA is derived from natural products. In sensory pharmacology, capsaicin (the pungent principle in hot chili peppers) and its ultrapotent analog, resiniferatoxin, are useful tools to dissect the pain pathway. Drs. Man-Kyo Chung and James Campbell summarize the sensory and physiological effects of capsaicin (a natural TRPV1 agonist) and the rationale of its therapeutic use [5]. They describe how the short-term excitatory effects of capsaicin (characterized by pungency or pain) are followed by a lasting refractory state in which the previously excited neurons are unresponsive to various unrelated stimuli. Mechanisms underlying capsaicin-induced analgesia both in the form of desensitization and denervation are discussed, along with potential clinical implications. Dr. Dorothy Cimino-Brown continues the theme of TRPV1 agonism by discussing the therapeutic potential of the ultrapotent TRPV1 agonist, resiniferatoxin, as a “molecular scalpel” to achieve permanent pain relief [6]. The review recounts both preclinical studies (including bone cancer