Neurochemical Research

, Volume 16, Issue 11, pp 1213–1218 | Cite as

5,8-Disubstituted indolizidines: A new class of noncompetitive blockers for nicotinic receptor-channels

  • John W. Daly
  • Yukio Nishizawa
  • William L. Padgett
  • Takashi Tokuyama
  • Adrian L. Smith
  • Andrew B. Holmes
  • Chihiro Kibayashi
  • Robert S. Aronstam
Original Articles


A series of 8-methyl-5-substituted indolizidines inhibit binding of the noncompetitive blocking agent [3H]perhydrohistrionicotoxin to muscle-type nicotinic acetylcholine receptor-channels in membranes fromTorpedo electroplax. The Ki values range from 0.16 to 1.12 μM, making these alkaloids among the most potent ligands for this site. Unlike most noncompetitive blockers, the potencies of the 8-methyl-5-substituted indolizidines arereduced in the presence of carbamylcholine. Indolizidine 205A (8-methyl-5-(4-pentynyl)indolizidine) is unique in enhancing binding of [3H]perhydrohistrionicotoxin by 1.5-fold. The enhancement is at a maximum at 0.01 to 0.1 μM, followed by progressive inhibition with an IC50 of about 20 μM. In the presence of carbamylcholine, which itself enhances binding of [3H]perhydrohistrionicotoxin, indolizidine 205A causes only an inhibition of binding with an IC50 of about 10 μM. Indolizidines with a hydroxy substituent on the 8-methyl group have very low activity. None of the indolizidines affect binding of [125I]α-bungarotoxin to acetylcholine recognition sites. In pheochromocytoma PC12 cells, indolizidine 205A has no agonist activity, but only inhibits carbamylcholine-elicited22Na+ influx. The profile of potencies for the 8-methyl-5-substituted indolizidines is similar in electroplax membranes and PC12 cells. Indolizidines 205A and 209B (8-methyl-5-pentylindolizidine) have no apparent effect on desensitization of receptors in PC12 cells. The 5,8-disubstituted indolizidines appear to represent an atypical and potent class of noncompetitive blockers for muscle-type and ganglionic nicotinic receptor-channels.

Key Words

Acetylcholine receptors indolizidines noncompetitive blockers 


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Copyright information

© Plenum Publishing Corporation 1991

Authors and Affiliations

  • John W. Daly
    • 1
  • Yukio Nishizawa
    • 1
  • William L. Padgett
    • 1
  • Takashi Tokuyama
    • 2
  • Adrian L. Smith
    • 3
  • Andrew B. Holmes
    • 3
  • Chihiro Kibayashi
    • 4
  • Robert S. Aronstam
    • 5
  1. 1.Laboratory of Bioorganic ChemistryNational Institutes of HealthBethesda
  2. 2.Faculty of ScienceOsaka City UniversityOsakaJapan
  3. 3.University Chemical LaboratoryUniversity of CambridgeCambridgeEngland
  4. 4.Tokyo College of PharmacyTokyoJapan
  5. 5.Department of Pharmacology and ToxicologyMedical College of GeorgiaAugusta

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