“Philanthotoxin”的意思、由来-开放百科全书

Philanthotoxins reversibly inhibit AMPA (also called the "quisqualate receptor"), kainate, and NMDA ionotropic glutamate receptors.^[3] Philanthotoxins have a hydrophobic aromatic head group and a hydrophilic polyamine tail, which allow them to inhibit iGluRs by binding within the ion channel.^[6] Inhibition may also occur via binding to an external allosteric polyamine binding site.^[5] Subunit composition of iGluRs heavily influences the efficacy of philanthotoxins. For example, AMPA receptors lacking the GluA2 subunit are highly sensitive to PhTX-433, whereas receptors containing the GluA2 subunit are nearly entirely insensitive.^[3] In addition, PhTX-433 inhibits both vertebrate and insect nAChRs predominantly by non-competitively blocking the ion channel in its open conformation.^[7]^[8]

Isolation and synthesis

PhTX-433 was structurally elucidated and subsequently synthesized in 1988 by Eldefrawi and colleagues.^[9] Because PhTX-433 lacks strong receptor subtype selectivity, a variety of analogs have been synthesized as candidates for potential pharmacological exploitation.^[6] Philanthotoxins have four distinct regions that can be modified (see image at right); the number of nitrogens in the polyamine chain is the most common distinction between synthetic analogs.^[6] The most commonly synthesized and studied analogue is PhTX-343, which has similar properties to PhTX-433.^[6]

Uses

Analogues with IC₅₀ values in the low nano-molar and pico-molar range have been identified and studied.^[6] Combined with the potential for precise receptor subtype selectivity, synthetic philanthotoxins could be used as highly potent and selective inhibitors for nAChRs and iGluRs. Glutamate is the main excitatory neurotransmitter in the mammalian brain and has been implicated in mediating neurological disorders such as epilepsy and neurodegenerative diseases such as Huntington's disease.^[9] Therefore, there is considerable interest in the therapeutic development of iGluR antagonists as anticonvulsants, muscle relaxants, and agents to protect from ischemic brain damage and possibly neurodegeneration.^[9] In addition, because nAChRs are the major excitatory neurotransmitter gated ion channels in insects, philanthotoxins may be developed as insecticides.^[9]^[6]

References

1. ^{{cite journal|last1=Strømgaard|first1=K.|last2=Jensen|first2=L. S.|last3=Vogensen|first3=S. B.|title=Polyamine toxins: development of selective ligands for ionotropic receptors|journal=Toxicon|date=2005|volume=45|issue=3|pages=249–254|url=http://www.sciencedirect.com/science/article/pii/S0041010104004647|accessdate=23 April 2017|doi=10.1016/j.toxicon.2004.11.013}}
2. ^{{cite journal|last1=Piek|first1=T.|title=δ-Philanthotoxin, a semi-irreversible blocker of ion-channels|journal=Comparative Biochemistry and Physiology Part C: Comparative Pharmacology|date=1982|volume=72|issue=2|pages=311–315|doi=10.1016/0306-4492(82)90098-3}}
3. ^¹²{{cite journal|last1=Kachel|first1=H.S.|last2=Patel|first2=R.N.|last3=Franzyk|first3=H.|last4=Mellor|first4=I.R.|title=Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition|journal=Scientific Reports|date=2016|volume=6|doi=10.1038/srep38116}}
4. ^{{cite journal|last2=Bukownik|first2=R.|last3=Eldefrawi|first3=A. T.|last4=Eldefrawi|first4=M. E.|last5=Goodnow|first5=R.|last6=Kallimopoulos|first6=T.|last7=Konno|first7=K.|last8=Nakanishi|first8=K.|last9=Niwa|first9=M.|date=1990|title=Structure-activity relationships of analogues of the wasp toxin philanthotoxin: non-competitive antagonists of quisqualate receptors|journal=Toxicon|volume=28|pages=11|last1=Bruce|first1=M.|last10=Usherwood|first10=P. N. R.|doi=10.1016/0041-0101(90)90098-r}}
5. ^¹{{cite journal|last2=Sherby|first2=S.|last3=Goodnow|first3=R.|last4=Niwa|first4=M.|last5=Konno|first5=K.|last6=Kallimopoulos|first6=T.|last7=Bukownik|first7=R.|last8=Nakanishi|first8=K.|last9=Usherwood|first9=P.|date=1990|title=Structure-activity relationships of philanthotoxin analogs and polyamines on N-methyl-D-aspartate and nicotinic acetylcholine receptors|journal=Journal of Pharmacology and Experimental Therapeutics|volume=254|issue=3|last1=Anis|first1=N.|last10=Eldefrawi|first10=A.}}
6. ^¹²³⁴⁵{{cite book|last1=Kachel|first1=H.|title=Inhibition of mammalian nicotinic acetylcholine receptors by philanthotoxin analogues is strongly influenced by subunit composition|date=2015|publisher=Nottingham ePrints}}
7. ^{{cite journal|last2=Usherwood|first2=P. N.|last3=Hess|first3=G. P.|date=1999|title=Inhibition of nicotinic acetylcholine receptor by philanthotoxin-343: kinetic investigations in the microsecond time region using a laser-pulse photolysis technique|journal=Biochemistry|volume=38|issue=35|pages=11406–11414|last1=Jayaraman|first1=V.|doi=10.1021/bi991219x}}
8. ^{{Cite journal|last=Rozental|first=R.|last2=Scoble|first2=G. T.|last3=Albuquerque|first3=E. X.|last4=Idriss|first4=M.|last5=Sherby|first5=S.|last6=Sattelle|first6=D. B.|last7=Nakanishi|first7=K.|last8=Konno|first8=K.|last9=Eldefrawi|first9=A. T.|date=1989-04-01|title=Allosteric inhibition of nicotinic acetylcholine receptors of vertebrates and insects by philanthotoxin.|url=http://jpet.aspetjournals.org/content/249/1/123|journal=Journal of Pharmacology and Experimental Therapeutics|language=en|volume=249|issue=1|pages=123–130|issn=0022-3565|pmid=2468760}}
9. ^¹²³{{cite journal|last1=Eldefrawi|first1=A. T.|last2=Eldefrawi|first2=M. E.|last3=Konno|first3=K.|last4=Mansour|first4=N.A.|last5=Nakanishi|first5=E.|last6=Oltz|first6=E.|last7=Usherwood|first7=P. N. R.|title=Structure and synthesis of a potent glutamate receptor antagonist in wasp venom|journal=Proc. Natl. Acad. Sci. U.S.A.|date=1988|volume=85|page=4910|doi=10.1073/pnas.85.13.4910|pmc=280547}}

Mechanism of Action

Isolation and synthesis

Uses

References