Evaluation of 8 Alkaloids for Activity at Neuronal Alpha BUNGAROTOXIN SITES



ION CHANNEL and RECEPTOR LIGANDS
TOXINS & ALKALOIDS

Evaluation of 8 Alkaloids for Activity at Neuronal Alpha BUNGAROTOXIN SITES
   
 
 
Dr. S. Wonnacott, School of Biology and Biochemistry, University of Bath, UK
  Neuronal nicotinic acetylcholine receptors (nAChR) are heterogeneous with respect to subunit composition, brain distribution and pharmacology. Alpha Bungarotoxin is selective for a subtype of neuronal nAChR that probably incorporates the Alpha7 subunit. This neuronal nAChR is distinct from muscle nAChR, although the latter also binds Alpha Bungarotoxin with high affinity. However, muscle and brain Alpha Bungarotoxin-sensitive nAChR can be discriminated by the natural product Methyllycaconitine (MLA). MLA has nanomolar affinity at the brain sites, compared with micromolar affinity at muscle nAChR and at Alpha Bungarotoxin-insensitive neuronal nAChR [Ward et al., FEBS Lett. 270:45 (1990)]. Because several natural products marketed by LATOXAN have some structural similarities with MLA, it is of interest to ascertain if they have activity at MLA-sensitive neuronal nAChR, defined by specific [125I] Alpha Bungarotoxin binding to brain membranes.

The compounds were made up in ethanol and serial dilutions in buffer were assayed for competition for [125I] Alpha Bungarotoxin binding to rat brain membranes, as previously described [MacAllan et al., FEBS Lett. 226:357 (1988)]. Each drug was assayed at least twice. IC50 values were determined by linear regression of Hill plots.
 
Results : IC50 values at brain [125I] Alpha Bungarotoxin binding sites.
 
 
Prod. No. DESCRIPTION IC50(M)
L6017 CONDELPHINE 3.6 x 10-6
L6052 DELCORINE 5.0 x 10-5
L6019 DELSOLINE 1.3 x 10-5
L6034 KARAKOLINE 1.0 x 10-6
L6037 NUDIKAULINE PERCHLORATE 5.0 x 10-9
L6057 DELTALINE 1.3 x 10-4
L6035 N-DESACETYLLAPPACONITINE 4.7 x 10-6
L6010 LAPPACONITINE HYDROBROMIDE 8.0 x 10-5
   
  Nudikauline is exceptionally potent: 200 times more potent than the next most active compound, Karakoline. Nudikauline is comparable to Methyllycaconitine in terms of its IC50 and the two compounds are closely related structurally.

The other Nicotinic compounds all lack the phenylsuccinamide sidechain and have only modest [125I] Alpha Bungarotoxin binding activity.

Of the three Na+ channel blockers N-Desactyllappaconitine has significant nicotinic activity, with an IC50 of 4.7 µM. Lappaconitine and Deltaline are 17 and 28 times less potent, and an IC50>10-4 M is not considered to be specific.

 
 
 

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