Page last updated: 2024-11-07

methyllycaconitine

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Description

Methyllycaconitine (MLA) is a potent and selective inhibitor of the α7 nicotinic acetylcholine receptor (α7nAChR), a protein found in the brain and other tissues. MLA is a natural product isolated from the plant Aconitum lycoctonum. Its complex structure has been a challenge to synthesize, but several synthetic routes have been developed. MLA has been shown to have a variety of effects, including anti-inflammatory, analgesic, and neuroprotective properties. Its ability to modulate α7nAChR activity makes it a promising candidate for the treatment of Alzheimer's disease, schizophrenia, and other neurological disorders. MLA is also being investigated for its potential use in treating pain, inflammation, and cancer.'

methyllycaconitine: natural toxin from seeds of Delphinium brownii; parasympathomimetic and mild nicotine antagonist; antagonist of alpha-conotoxin-MII sensitive presynaptic nicotinic receptors; potent insecticide; RN refers to (1alpha,4(S),6beta,14alpha,16beta)-isomer [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

FloraRankFlora DefinitionFamilyFamily Definition
DelphiniumgenusA plant genus of the family RANUNCULACEAE. Members contain ACONITINE and other diterpenoid alkaloids.[MeSH]RanunculaceaeThe buttercup plant family of the order RANUNCULALES, class MAGNOLIOPSIDA. The leaves are usually alternate and stalkless. The flowers usually have two to five free sepals and may be radially symmetrical or irregular.[MeSH]

Cross-References

ID SourceID
PubMed CID107640
MeSH IDM0154161

Synonyms (11)

Synonym
lycaconitine, methyl-
delartine
aconitane-7,8-diol, 20-ethyl-4-(((2-(3-methyl-2,5-dioxo-1-pyrrolidinyl)benzoyl)oxy)methyl)-1,6,14,16-tetramethoxy-, (1-alpha,4(s),6-beta,14-alpha,16-beta)-
delsemidine
brn 0076234
aconitane-7,8-diol, 20-ethyl-1,6,14,16-tetramethoxy-4-(((2-(3-methyl-2,5-dioxo-1-pyrrolidinyl)benzoyl)oxy)methyl)-, (1alpha,4(s),6beta,14alpha,16beta)-
methyllycaconitine
21019-30-7
8h7ex9z9qe ,
unii-8h7ex9z9qe
4-21-00-04589 (beilstein handbook reference)

Research Excerpts

Overview

Methyllycaconitine is a norditerpenoid alkaloid found in high abundance in toxic Delphinium (larkspur) species. It is a competitive antagonist of nicotinic acetylcholine receptors, with a remarkable preference for neuronal [125I]alpha Bgt binding sites.

ExcerptReferenceRelevance
"Methyllycaconitine (MLA) is a norditerpenoid alkaloid found in high abundance in toxic Delphinium (larkspur) species. "( Potentiation of the actions of acetylcholine, epibatidine, and nicotine by methyllycaconitine at fetal muscle-type nicotinic acetylcholine receptors.
Cook, D; Gardner, DR; Green, BT; Welch, KD, 2011
)
2.04
"Methyllycaconitine (MLA) is a selective and potent antagonist of the α7 nAChR, and its anthranilate ester side-chain is important for its activity."( Identifying the binding site of novel methyllycaconitine (MLA) analogs at α4β2 nicotinic acetylcholine receptors.
Absalom, N; Ambrus, JI; Chebib, M; Halliday, JI; Lin, D; Lochner, M; Lummis, SC; McLeod, MD; Quek, GX; Thompson, AJ, 2010
)
1.35
"Methyllycaconitine (MLA) is a competitive antagonist of nicotinic acetylcholine receptors, with a remarkable preference for neuronal [125I]alpha Bgt binding sites. "( Conversion of the sodium channel activator aconitine into a potent alpha 7-selective nicotinic ligand.
Blagbrough, IS; Cooper, G; Hardick, DJ; Potter, BV; Scott-Ward, T; Wonnacott, S, 1995
)
1.73
"Methyllycaconitine (MLA, 1) is a novel, potent probe for mammalian and insect nicotinic acetylcholine receptors (nAChR) and displays remarkable selectivity toward neuronal [125I]-alpha-bungarotoxin (alpha BgTX) binding sites that correspond to alpha 7-type nAChR in mammalian brain. "( Nudicauline and elatine as potent norditerpenoid ligands at rat neuronal alpha-bungarotoxin binding sites: importance of the 2-(methylsuccinimido)benzoyl moiety for neuronal nicotinic acetylcholine receptor binding.
Blagbrough, IS; Cooper, G; Critchley, T; Hardick, DJ; Potter, BV; Wonnacott, S, 1996
)
1.74
"[3H]-Methyllycaconitine ([3H]-MLA) is a new radioligand with selectivity for alpha7-type neuronal nicotinic acetylcholine receptors (nAChRs). "( An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain.
Blagbrough, IS; Collins, AC; Davies, AR; Marks, MJ; Potter, BV; Whiteaker, P; Wolstenholme, AJ; Wonnacott, S, 1999
)
1.03

Treatment

Methyllycaconitine (3 mg/kg), an α7 nAChR antagonist, reversed TQS-induced decrease in IκB and CD11b mRNA expressions in the hippocampus. Pretreatment with methyllycaconsitine citrate significantly attenuated cytisine-induced sympathetic response with little effect on the parasympathetic response.

ExcerptReferenceRelevance
"Pretreatment of methyllycaconitine (3 mg/kg), an α7 nAChR antagonist, reversed TQS-induced decrease in IκB and CD11b mRNA expressions in the hippocampus indicating the involvement of α7 nAChR."( The α7 nicotinic acetylcholine receptor positive allosteric modulator attenuates lipopolysaccharide-induced activation of hippocampal IκB and CD11b gene expression in mice.
Abbas, M; Alzarea, S; Papke, RL; Rahman, S,
)
0.47
"Pretreatment of methyllycaconitine (3 mg/kg, i.p.), an α7 nAChR antagonist, significantly prevented the antidepressant-like effects of PNU (4 mg/kg)."( Effects of alpha-7 nicotinic allosteric modulator PNU 120596 on depressive-like behavior after lipopolysaccharide administration in mice.
Alzarea, S; Rahman, S, 2018
)
0.81
"Pretreatment with methyllycaconitine citrate, a selective alpha7 nicotinic receptor antagonist, significantly attenuated cytisine-induced sympathetic response with little effect on the parasympathetic response."( Cytisine induces autonomic cardiovascular responses via activations of different nicotinic receptors.
Freeling, J; Lacroix, C; Li, YF, 2010
)
0.68
"Pretreatment with methyllycaconitine citrate (MLA), alpha-bungarotoxin, or atropine blocked the antinociception of choline in the hot plate test."( Antinociceptive effects of choline against acute and inflammatory pain.
Liu, Y; Su, DM; Wang, H; Wang, RH; Wang, Y, 2005
)
0.65

Toxicity

ExcerptReferenceRelevance
" Expression of mutant alpha7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell lines SH-SY5Y and IMR-32, but not to several other cell types."( Neurotoxicity of channel mutations in heterologously expressed alpha7-nicotinic acetylcholine receptors.
Bertrand, D; Buisson, B; Changeux, JP; Fryer, JD; Galzi, JL; Lucero, L; Lukas, RJ; Puchacz, E, 2001
)
0.31
" Mice were injected with several larkspur toxin-protein conjugates or adjuvant alone to determine whether the resulting immunological response altered animal susceptibility to methyllycaconitine, the major toxic larkspur alkaloid."( Evaluation of vaccination against methyllycaconitine toxicity in mice.
Gardner, DR; James, LF; Lee, ST; Panter, KE; Pfister, JA; Schoch, TK; Stegelmeier, BL, 2003
)
0.79
" In addition to the stimulatory effects of both ethanol and nicotine on the mesolimbic reward pathway, nicotine's ability to counteract some of the adverse effects of ethanol (e."( Protective effects of nicotine on ethanol-induced toxicity in cultured cerebellar granule cells.
Al-Namaeh, M; Manaye, KF; Taylor, RE; Tizabi, Y, 2003
)
0.32
" Given that cigarette smoking is highly prevalent in some of these patient groups and nicotine has been shown to reduce toxic consequences of NMDA receptor function, it may be suggested that nicotine intake may attenuate the neurotoxic effects of hypercortisolemia."( (-)-nicotine ameliorates corticosterone's potentiation of N-methyl-d-aspartate receptor-mediated cornu ammonis 1 toxicity.
Harris, BR; Littleton, JM; Mulholland, PJ; Prendergast, MA; Self, RL, 2004
)
0.32
" The MSAL-type alkaloids are generally much more toxic (typically >20 times)."( The effect of 7,8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of methyllycaconitine in mice.
Cook, D; Gardner, DR; Green, BT; Panter, KE; Pfister, JA; Stegelmeier, BL; Welch, KD, 2008
)
0.57
" Larkspur's toxicity has been attributed to the norditerpenoid alkaloids, which are divided into two main structural groups: the highly toxic (N-methylsuccinimido) anthranoyllycoctonine type (MSAL type) and the less toxic 7,8-methylenedioxylycoctonine type (MDL type)."( The biogeographical distribution of duncecap larkspur (Delphinium occidentale) chemotypes and their potential toxicity.
Cook, D; Gardner, DR; Green, BT; Lee, ST; Pfister, JA; Welch, KD, 2009
)
0.35
" The steroidal alkaloid zygacine is believed to be the primary toxic component in death camas."( The acute toxicity of the death camas (Zigadenus species) alkaloid zygacine in mice, including the effect of methyllycaconitine coadministration on zygacine toxicity.
Cook, D; Gardner, DR; Green, BT; Panter, KE; Pfister, JA; Stegelmeier, BL; Welch, KD, 2011
)
0.58

Pharmacokinetics

ExcerptReferenceRelevance
" The method was successfully applied to quantify MLA concentrations in a rodent pharmacokinetic and brain penetration study."( Quantification of methyllycaconitine, selective α7 nicotinic receptor antagonist, in rodent plasma and brain tissue by liquid chromatography tandem mass spectrometry--application to neuropharmacokinetics of methyllycaconitine in rats.
Aleti, R; Bhyrapuneni, G; Boggavarapu, R; Kandikere, V; Komarneni, P; Muddana, N; Mukkanti, K; Nirogi, R, 2011
)
0.7

Bioavailability

ExcerptReferenceRelevance
") administration and poor bioavailability following oral (p."( A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain.
Arneric, SP; Campbell, JE; Kang, CH; Sullivan, JP; Turek, JW,
)
0.34
" Furthermore, the compounds are tertiary amines, implying some advantages in terms of bioavailability pertinent to future in vivo pharmacological studies."( Carbamoylcholine homologs: novel and potent agonists at neuronal nicotinic acetylcholine receptors.
Bräuner-Osborne, H; Falch, E; Frølund, B; Jensen, AA; Krogsgaard-Larsen, P; Mikkelsen, I, 2003
)
0.32
" Coadministration of mixtures did not result in increased MLA bioavailability or alterations in clearance from the brain and muscle."( The effect of 7,8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of methyllycaconitine in mice.
Cook, D; Gardner, DR; Green, BT; Panter, KE; Pfister, JA; Stegelmeier, BL; Welch, KD, 2008
)
0.57
" The results from this study indicate that the toxic alkaloids in larkspurs undergo flip-flop kinetics, meaning the rate of absorption of the alkaloids is slower than the rate of elimination."( Serum toxicokinetics after intravenous and oral dosing of larkspur toxins in goats.
Gardner, DR; Green, BT; Pfister, JA; Stonecipher, CA; Welch, KD, 2017
)
0.46

Dosage Studied

ExcerptRelevanceReference
" The nicotine discrimination was acquired successfully and nicotine yielded a steep dose-response curve."( Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice.
Gommans, J; Shoaib, M; Stolerman, IP, 2000
)
0.31
" Nefiracetam potentiated alpha4beta2-like ACh- and NMDA-induced currents at nanomolar concentrations forming bell-shaped dose-response curves with the maximum potentiation occurring at 1 and 10 nM, respectively."( Unique mechanism of action of Alzheimer's drugs on brain nicotinic acetylcholine receptors and NMDA receptors.
Marszalec, W; Moriguchi, S; Narahashi, T; Yeh, JZ; Zhao, X, 2003
)
0.32
" Both nicotine and the nicotinic alpha-7 selective agonist AR-17779 significantly increased cell proliferation albeit with bell-shaped dose-response kinetics."( Nicotine regulates SH-SY5Y neuroblastoma cell proliferation through the release of brain-derived neurotrophic factor.
Carney, SL; Serres, F, 2006
)
0.33
" This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%)."( Activation of the alpha7-nicotinic acetylcholine receptor reverses complete freund adjuvant-induced mechanical hyperalgesia in the rat via a central site of action.
Billinton, A; Bingham, S; Chessell, IP; Clayton, NM; Hatcher, JP; Hille, CJ; Medhurst, SJ, 2008
)
0.6
"3 mg/kg) not previously tested on attention improved response accuracy, resulting in an inverted U-shape dose-response function."( Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement.
Hahn, B; Shoaib, M; Stolerman, IP, 2011
)
0.37
" Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS."( Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
Gill, JK; Millar, NS; Savolainen, M; Sher, E; Young, GT; Zwart, R, 2011
)
0.37
" In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters."( 3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors.
Camarasa, J; Escubedo, E; Garcia-Ratés, S; Pubill, D, 2013
)
0.39
"Low and high doses of NIC, cytisine (CYT), CC4 and CC26 respectively improved and worsened the mean running time, showing an inverted U dose-response function."( Role of neuronal nicotinic acetylcholine receptors (nAChRs) on learning and memory in zebrafish.
Braida, D; Gotti, C; Martucci, R; Ponzoni, L; Sala, M; Sparatore, F, 2014
)
0.4
" However, most of the pen studies conducted thus far have used a dosing regimen of a single bolus dose, which does not accurately mimic the manner by which cattle are poisoned by larkspur while grazing."( The effect of administering multiple doses of tall larkspur (Delphinium barbeyi) to cattle.
Cook, D; Gardner, DR; Green, BT; Pfister, JA; Welch, KD, 2015
)
0.42
" However, those studies were all performed by orally dosing plant material."( Serum toxicokinetics after intravenous and oral dosing of larkspur toxins in goats.
Gardner, DR; Green, BT; Pfister, JA; Stonecipher, CA; Welch, KD, 2017
)
0.46
" Clinical signs of intoxication, including muscle coordination and function, were measured 24 h after oral dosing with larkspur by walking the cattle at a pace of 5 to 6 km h-1 for up to 40 min on an oval dirt track."( Sex-dependent differences for larkspur (Delphinium barbeyi) toxicosis in yearling Angus cattle1.
Bennett, GL; Cook, D; Davis, TZ; Gardner, DR; Green, BT; Keele, JW; Lee, ST; Pfister, JA; Stegelmeier, BL; Stonecipher, CA; Welch, KD, 2019
)
0.51
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (404)

TimeframeStudies, This Drug (%)All Drugs %
pre-19901 (0.25)18.7374
1990's58 (14.36)18.2507
2000's187 (46.29)29.6817
2010's138 (34.16)24.3611
2020's20 (4.95)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 30.52

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be moderate demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index30.52 (24.57)
Research Supply Index6.03 (2.92)
Research Growth Index6.91 (4.65)
Search Engine Demand Index35.70 (26.88)
Search Engine Supply Index2.00 (0.95)

This Compound (30.52)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials0 (0.00%)5.53%
Reviews2 (0.48%)6.00%
Case Studies0 (0.00%)4.05%
Observational0 (0.00%)0.25%
Other412 (99.52%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]