Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs

Abstract

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.

The Tunicate Metabolite 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine Targets Ion Channels of Vertebrate Sensory Neurons

“…The sensory neurons of the DRG represent many cell types that are specialized to relay specific sensory information to the central nervous system. Previous work has defined 16 specific cell types in the DRGs, used to screen ligands for the management of neuropathic pain. , Here, we identified and characterized one of the bioactive ligands from our library of marine natural products, DIMTA (Figure ). The compound was active in constellation pharmacology assays performed on dissociated neurons from the mouse DRG, selectively targeting just one of the cell types (LTCTs) at lower doses (Figure ).…”

Marine natural products

“…A series of polymeric MNPs, molleamines A–E 1444–1448 were isolated from the Pleurobranch mollusc Pleurobranchus forskalii . 617 Molleamine C was identified as being capable of blocking acetylcholine-induced calcium influx while electrophysiology experiments determined it to be a weak partial antagonist of α3β4 and α6/α3β4 nAChR's. A Brazilian collection of the nudibranch Roboastra ernesti was the source of tambjamines M–O 1449–1451 , identified during a metabolomics-driven MS/MS study with the structures confirmed by synthesis.…”

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

“…As shown above, nAChR agonists from marine sources could have a tremendous effect on the drug design field. A few novel marine nAChR agonists have been discovered in recent years, including 6-bromohypaphorine from the nudibranch mollusk Hemissena crassicornis, targeting α7 nAChR [ 93 ] and molleamines [ 94 ]. The latter have recently been shown to be partial agonists at α3- and α6-containing nAChRs expressed in dorsal root ganglions [ 94 ].…”

“…A few novel marine nAChR agonists have been discovered in recent years, including 6-bromohypaphorine from the nudibranch mollusk Hemissena crassicornis, targeting α7 nAChR [ 93 ] and molleamines [ 94 ]. The latter have recently been shown to be partial agonists at α3- and α6-containing nAChRs expressed in dorsal root ganglions [ 94 ]. Moreover, signs of antinociceptive activity and the lack of acute toxicity make molleamines promising hits for drug design.…”