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Gina F Marrone, Zhigang Lu, Grace Rossi, Ankita Narayan, Amanda Hunkele, Sarah Marx, Jin Xu, John Pintar, Susruta Majumdar, Ying-Xian Pan, Gavril W Pasternak
The mu opioid receptor gene undergoes extensive alternative splicing. Mu opioids can be divided into three classes based on the role of different groups of splice variants. Morphine and methadone require only full length seven transmembrane (7TM) variants for analgesia, whereas IBNtxA (3'-iodobenzyol-6β-naltrexamide) needs only truncated 6TM variants. A set of endomorphin analogs fall into a third group that requires both 6TM and 7TM splice variants. Unlike morphine, endomorphin 1 and 2, DAPP (Dmt,d-Ala-Phe-Phe-NH2), and IDAPP (3'-iodo-Dmt-d-Ala-Phe-Phe-NH2) analgesia was lost in an exon 11 knockout mouse lacking 6TM variants...
October 10, 2016: ACS Chemical Neuroscience
Gina F Marrone, Steven G Grinnell, Zhigang Lu, Grace C Rossi, Valerie Le Rouzic, Jin Xu, Susruta Majumdar, Ying-Xian Pan, Gavril W Pasternak
The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects...
March 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
András Váradi, Gina F Marrone, Shainnel O Eans, Michelle L Ganno, Joan J Subrath, Valerie Le Rouzic, Amanda Hunkele, Gavril W Pasternak, Jay P McLaughlin, Susruta Majumdar
3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0...
November 18, 2015: ACS Chemical Neuroscience
Zhigang Lu, Jin Xu, Grace C Rossi, Susruta Majumdar, Gavril W Pasternak, Ying-Xian Pan
The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-opioid receptor splice variants...
July 1, 2015: Journal of Clinical Investigation
Jeffrey S Wieskopf, Ying-Xian Pan, Jaclyn Marcovitz, Alexander H Tuttle, Susruta Majumdar, John Pidakala, Gavril W Pasternak, Jeffrey S Mogil
μ-Opioids remain vastly important for the treatment of pain, and would represent ideal analgesics if their analgesic effects could be separated from their many side effects. A recently synthesized compound, iodobenzoylnaltrexamide (IBNtxA), acting at 6-transmembrane (6-TM) splice variants of the μ-opioid receptor gene, was shown to have potent analgesic actions against acute, thermal pain accompanied by a vastly improved side-effect profile compared to 7-TM-acting drugs such as morphine. Whether such analgesia can be seen in longer-lasting and nonthermal algesiometric assays is not known...
October 2014: Pain
Steven G Grinnell, Susruta Majumdar, Ankita Narayan, Valerie Le Rouzic, Michael Ansonoff, John E Pintar, Gavril W Pasternak
IBNtxA (3'-iodobenzoyl-6β-naltrexamide) is a potent analgesic in mice lacking many traditional opioid side effects. In mice, it displays no respiratory depression, does not produce physical dependence with chronic administration, and shows no cross-tolerance to morphine. It has limited effects on gastrointestinal transit and shows no reward behavior. Biochemical studies indicate its actions are mediated through a set of μ-opioid receptor clone MOR-1 splice variants associated with exon 11 that lack exon 1 and contain only six transmembrane domains...
September 2014: Journal of Pharmacology and Experimental Therapeutics
Susruta Majumdar, Joan Subrath, Valerie Le Rouzic, Lisa Polikar, Maxim Burgman, Kuni Nagakura, Julie Ocampo, Nathan Haselton, Anna R Pasternak, Steven Grinnell, Ying-Xian Pan, Gavril W Pasternak
3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity...
July 26, 2012: Journal of Medicinal Chemistry
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