Open AccessNicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs
Author(s) -
Noemi D. Paguigan,
Jortan O. Tun,
Lee S. Leavitt,
Zhenjian Lin,
Kevin Chase,
Cheryl Dowell,
Cassandra E. Deering-Rice,
Albebson L. Lim,
M. Karthikeyan,
Ronald W. Hughen,
Jie Zhang,
Randall T. Peterson,
Christopher A. Reilly,
Alan R. Light,
Shrinivasan Raghuraman,
J. Michael McIntosh,
Baldomero M. Olivera,
Eric W. Schmidt
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00345
Subject(s) - acetylcholine , muscarinic acetylcholine receptor , nicotinic agonist , muscarinic acetylcholine receptor m3 , acetylcholine receptor , chemistry , partial agonist , cholinergic , muscarinic acetylcholine receptor m4 , biology , pharmacology , agonist , endocrinology , receptor , biochemistry
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 IC 50 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.