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Mar Drugs
2015 Mar 12;133:1255-66. doi: 10.3390/md13031255.
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6-bromohypaphorine from marine nudibranch mollusk Hermissenda crassicornis is an agonist of human α7 nicotinic acetylcholine receptor.
Kasheverov IE
,
Shelukhina IV
,
Kudryavtsev DS
,
Makarieva TN
,
Spirova EN
,
Guzii AG
,
Stonik VA
,
Tsetlin VI
.
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6-Bromohypaphorine (6-BHP) has been isolated from the marine sponges Pachymatisma johnstoni, Aplysina sp., and the tunicate Aplidium conicum, but data on its biological activity were not available. For the nudibranch mollusk Hermissenda crassicornis no endogenous compounds were known, and here we describe the isolation of 6-BHP from this mollusk and its effects on different nicotinic acetylcholine receptors (nAChR). Two-electrode voltage-clamp experiments on the chimeric α7 nAChR (built of chicken α7 ligand-binding and glycine receptor transmembrane domains) or on rat α4β2 nAChR expressed in Xenopus oocytes revealed no action of 6-BHP. However, in radioligand analysis, 6-BHP competed with radioiodinated α-bungarotoxin for binding to human α7 nAChR expressed in GH4C1 cells (IC50 23 ± 1 μM), but showed no competition on muscle-type nAChR from Torpedo californica. In Ca2+-imaging experiments on the human α7 nAChR expressed in the Neuro2a cells, 6-BHP in the presence of PNU120596 behaved as an agonist (EC50 ~80 μM). To the best of our knowledge, 6-BHP is the first low-molecular weight compound from marine source which is an agonist of the nAChR subtype. This may have physiological importance because H. crassicornis, with its simple and tractable nervous system, is a convenient model system for studying the learning and memory processes.
Figure 1. Chemical structure of l-6-Bromohypaphorine (6-BHP).
Figure 2. (A) Oocytes expressing chicken α7/GlyR chimera respond to application of 100 μM acetylcholine (ACh, black bars) but not to 10 or 100 μM 6-BHP (red bars). 6-BHP at 100 μM also did not inhibit acetylcholine-evoked current, while α-cobratoxin at 1 μM completely abolished it (α-CTX, green bar); (B) Oocytes expressing rat α4β2 nAChR respond to application of 10 μM epibatidine (epi, black bars) but not 100 μM 6-BHP (red bars), which at concentrations up to 100 μM did not inhibit epibatidine-evoked current, while DHβE at 1 μM completely abolished it (green bar). Bars show scale for time and current; (C) Dose-response curve for acetylcholine at chimeric α7/GlyR (EC50 = 80 ± 5 μM, n = 3–4); (D) Dose-response curve for epibatidine at α4β2 nAChR (EC50 = 190 ± 10 nM, n = 3–4).
Figure 3. Inhibition of initial rate for radioiodinated α-bungarotoxin ([125I]-αBgt) binding to human α7 nAChR (1, open circles) or muscle-type nAChR from T. californica (2, filled circles) with 6-BHP. Each point is a mean ± s.e.m. value of three measurements for each concentration in two independent experiments. The curve (1) for α7 nAChR expressed in the GH4C1 cells was calculated from the means ± s.e.m. using the ORIGIN 7.5 program (see Experimental Section). The respective IC50 = 23 ± 1 μM. Virtually no evident inhibition of [125I]-αBgt binding to T. californica nAChR was detected with 6-BHP at concentrations up to 1000 μM.
Figure 4. 6-Bromohypaphorine (6-BHP) from Hermissenda crassicornis provoked an intracellular calcium concentration rise ([Ca2+]i rise) in neuroblastoma Neuro2a cells expressing human α7 nAChR. (A) Normalized [Ca2+]i rise after application of 200 μM 6-BHP and its inhibition by 2-min preincubation with 2 μM α-cobratoxin (CTX), a specific antagonist of α7 nAChR; (B) A curve of [Ca2+]i rise in response to different concentrations of 6-BHP. All ligand solutions contained 10 μM PNU120596, a positive allosteric modulator of α7 nAChR. The calculated EC50 value was 82.7 ± 20.1 μM (mean ± s.e.m., n = 5).
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