Methylaplysinopsin: A Natural Product of Marine Origin With Effects on Serotonergic Neurotransmission

Abstract

1. Methylaplysinopsin is an indolyl-methylene derivative of creatinin which was isolated from a sponge collected on the Great Barrier Reef. 2. It is a potent inhibitor of tetrabenazine-induced responses in rats and mice and appears to act through several mechanisms, each of which enhances central serotonergic function. 3. As a reversible inhibitor of type A monoamine oxidase (MAO) methylaplysinopsin is relatively short-acting and has a Ki of 0.2 mumol/l when serotonin is the substrate used. 4. Methylaplysinopsin (10(-4) mol/l) also releases [3H]-serotonin from prelabelled synaptosomes, but has little effect on release of [3H]-noradrenaline ([3H]-NA) from a similar preparation. 5. In blocking uptake of [3H]-serotonin into cerebral cortical synaptosomes, methylaplysinopsin has a potency similar to that of imipramine (Ki = 2 X 10(-7) mol/l cf. 5 X 10(-7) mol/l), but it is considerably less potent in blocking [3H]-NA uptake. 6. Methylaplysinopsin is a weak displacer of [3H]-serotonin specific binding (IC50 = 160 mumol/l for hippocampal membrane preparations and 66 mumol/l for crude homogenates of rat brain). 7. Thus, methylaplysinopsin has effects on various aspects of serotonergic function. Whilst some of these effects are weak, they appear relatively selective for this neurochemical system.

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“…Methylaplysinopsin ( 1 ) (Fig. 2) isolated from Aplysinopsis reticulata by Baird-Lambert et al was reported to inhibit monoamine oxidase (MAO) and to displace serotonin from its receptors 16. Other molecules from this group: 6-bromo-2′-de- N -methylaplysinopsin ( 2 ), 6-bromoaplysinopsin ( 3 ), and N -3′-ethylaplysinopsin ( 4 ) (Fig.…”

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“…This activity was evaluated in tetrabenazine-induced ptosis in mice and rats. A pretreatment with methylaplysinopsin caused significant reduction in ptosis occurring in tetrabenazine treated rodents with ED 50 5 mg/kg [9,30]. Reversal of tetrabenazine ptosis has been also tested for other aplysinopsins [9].…”

“…An inhibition of monoamine oxidase (MAO), as well as an inhibition of the neuronal uptake of the neurotransmitters serotonin or noradrenalin, are common mechanisms accounting for the antidepressant effect [30]. In in vitro studies on mouse brain homogenate as a source of MAO, methylaplysinopsin exhibited enzyme inhibition over a wide concentration range (0.1–100 μM), especially with serotonin as a substrate.…”

“…The biological activity of that compound correlated also with its disappearance from the plasma. Pharmacokinetic studies on rats showed that after intravenous administration, methylaplysinopsin concentration in plasma declines rapidly over 4–8 h, reaching the level below 1 ng/mL 8 hours after dosing [30]. The relevant antidepressant activity achieved after intravenous and oral administration in mice suggested the presence of active metabolites of methylaplysinopsin.…”

“…The relevant antidepressant activity achieved after intravenous and oral administration in mice suggested the presence of active metabolites of methylaplysinopsin. However, the comprehensive pharmacokinetics studies were limited because of sensitivity of HPLC detection of the parent compound [30]. …”