Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs
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 to...
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| Veröffentlicht in: | ACS chemical neuroscience 2021-07, Vol.12 (14), p.2693-2704 |
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| creator | Paguigan, Noemi D Tun, Jortan O Leavitt, Lee S Lin, Zhenjian Chase, Kevin Dowell, Cheryl Deering-Rice, Cassandra E Lim, Albebson L Karthikeyan, Manju Hughen, Ronald W Zhang, Jie Peterson, Randall T Reilly, Christopher A Light, Alan R Raghuraman, Shrinivasan McIntosh, J. Michael Olivera, Baldomero M Schmidt, Eric W |
| description | 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. |
| doi_str_mv | 10.1021/acschemneuro.1c00345 |
| format | Article |
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Michael ; Olivera, Baldomero M ; Schmidt, Eric W</creator><creatorcontrib>Paguigan, Noemi D ; Tun, Jortan O ; Leavitt, Lee S ; Lin, Zhenjian ; Chase, Kevin ; Dowell, Cheryl ; Deering-Rice, Cassandra E ; Lim, Albebson L ; Karthikeyan, Manju ; Hughen, Ronald W ; Zhang, Jie ; Peterson, Randall T ; Reilly, Christopher A ; Light, Alan R ; Raghuraman, Shrinivasan ; McIntosh, J. Michael ; Olivera, Baldomero M ; Schmidt, Eric W</creatorcontrib><description>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.</description><identifier>ISSN: 1948-7193</identifier><identifier>EISSN: 1948-7193</identifier><identifier>DOI: 10.1021/acschemneuro.1c00345</identifier><identifier>PMID: 34213884</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>ACS chemical neuroscience, 2021-07, Vol.12 (14), p.2693-2704</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a426t-9659cb243e6ef6e0630fe12eeafc927c806ad7dc1fa56e6e86d4e59c9e274a403</citedby><cites>FETCH-LOGICAL-a426t-9659cb243e6ef6e0630fe12eeafc927c806ad7dc1fa56e6e86d4e59c9e274a403</cites><orcidid>0000-0002-2103-1194 ; 0000-0003-0727-3469 ; 0000-0002-5006-1982 ; 0000-0001-5839-694X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acschemneuro.1c00345$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acschemneuro.1c00345$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2751,27055,27903,27904,56716,56766</link.rule.ids></links><search><creatorcontrib>Paguigan, Noemi D</creatorcontrib><creatorcontrib>Tun, Jortan O</creatorcontrib><creatorcontrib>Leavitt, Lee S</creatorcontrib><creatorcontrib>Lin, Zhenjian</creatorcontrib><creatorcontrib>Chase, Kevin</creatorcontrib><creatorcontrib>Dowell, Cheryl</creatorcontrib><creatorcontrib>Deering-Rice, Cassandra E</creatorcontrib><creatorcontrib>Lim, Albebson L</creatorcontrib><creatorcontrib>Karthikeyan, Manju</creatorcontrib><creatorcontrib>Hughen, Ronald W</creatorcontrib><creatorcontrib>Zhang, Jie</creatorcontrib><creatorcontrib>Peterson, Randall T</creatorcontrib><creatorcontrib>Reilly, Christopher A</creatorcontrib><creatorcontrib>Light, Alan R</creatorcontrib><creatorcontrib>Raghuraman, Shrinivasan</creatorcontrib><creatorcontrib>McIntosh, J. Michael</creatorcontrib><creatorcontrib>Olivera, Baldomero M</creatorcontrib><creatorcontrib>Schmidt, Eric W</creatorcontrib><title>Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs</title><title>ACS chemical neuroscience</title><addtitle>ACS Chem. Neurosci</addtitle><description>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. 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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. 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| title | Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs |
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