Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs
| Autor: | Cheryl Dowell, Zhenjian Lin, Baldomero M. Olivera, Ronald W. Hughen, Randall T. Peterson, Albebson L. Lim, Jie Zhang, Kevin Chase, J. Michael McIntosh, Noemi D. Paguigan, Lee S. Leavitt, Eric W. Schmidt, Shrinivasan Raghuraman, Manju Karthikeyan, Christopher A. Reilly, Cassandra E. Deering-Rice, Jortan O. Tun, Alan R. Light |
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| Rok vydání: | 2021 |
| Předmět: |
Sympathetic nervous system
Superior cervical ganglion alpha7 Nicotinic Acetylcholine Receptor Physiology Cognitive Neuroscience Nicotinic Antagonists Receptors Nicotinic Pharmacology Biochemistry Article Mice Aplysia Muscarinic acetylcholine receptor Calcium flux medicine Animals Urochordata Acetylcholine receptor Chemistry Cell Biology General Medicine Rats Nylons Nicotinic acetylcholine receptor medicine.anatomical_structure Nicotinic agonist Acetylcholine medicine.drug |
| Zdroj: | ACS Chem Neurosci |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.1c00345 |
| Popis: | In our efforts to discover new drugs to treat pain, we identified molleamines A-E (1-5) as major neuroactive components of the sea slug, Pleurobranchus forskalii, and their prey, Didemnum molle, tunicates. The chemical structures of molleamines were elucidated by spectroscopy and confirmed by the total synthesis of molleamines A (1) and C (3). Synthetic 3 completely blocked acetylcholine-induced calcium flux in peptidergic nociceptors (PNs) in the somatosensory nervous system. Compound 3 affected neither the α7 nAChR nor the muscarinic acetylcholine receptors in calcium flux assays. In addition to nociceptors, 3 partially blocked the acetylcholine-induced calcium flux in the sympathetic nervous system, including neurons from the superior cervical ganglion. Electrophysiology revealed a block of α3β4 (mouse) and α6/α3β4 (rat) nicotinic acetylcholine receptors (nAChRs), with IC50 values of 1.4 and 3.1 μM, respectively. Molleamine C (3) is a partial antagonist, reaching a maximum block of 76-82% of the acetylcholine signal and showing no partial agonist response. Molleamine C (3) may thus provide a lead compound for the development of neuroactive compounds with unique biological properties. |
| Databáze: | OpenAIRE |
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