Synthesis, nicotinic acetylcholine receptor binding, antinociceptive and seizure properties of methyllycaconitine analogs.

Abstract

A series of methyllycaconitine (1a, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [(125)I]iodo-MLA binding at rat brain alpha7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [(3)H]epibatidine. At the alpha7 nAChR, MLA showed a K(i) value of 0.87 nM, analogs 1b-e possessed K(i) values of 1.67-2.16 nM, and 1f showed a K(i) value of 26.8 nM. Surprisingly, the analog 1e containing the large phenyl substituent (K(i)=1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50)=2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K(i)=1.78 nM at alpha7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50)=12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha7 nAChR antagonist and neuroprotection.

• Authors: F Ivy Carroll, Wei Ma, Hernán A Navarro, Philip Abraham, Scott A Wolckenhauer, M I Damaj, Billy R Martin
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 2 Pg. 678-85 (Jan 15 2007) ISSN: 0968-0896 [Print] England
• PMID: 17098430 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics
• Anticonvulsants
• Bridged Bicyclo Compounds, Heterocyclic
• Indicators and Reagents
• Nicotinic Agonists
• Pyridines
• Receptors, Nicotinic
• methyllycaconitine
• Nicotine
• epibatidine
• Aconitine

Topics

• Aconitine (analogs & derivatives, chemical synthesis, metabolism, pharmacology)
• Analgesics (chemical synthesis, pharmacology)
• Animals
• Anticonvulsants (chemical synthesis, pharmacology)
• Binding, Competitive (drug effects)
• Brain (metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (metabolism)
• Cerebral Cortex (drug effects, metabolism)
• Data Interpretation, Statistical
• In Vitro Techniques
• Indicators and Reagents
• Male
• Mice
• Mice, Inbred ICR
• Nicotine
• Nicotinic Agonists (metabolism)
• Pain Measurement (drug effects)
• Pyridines (metabolism)
• Rats
• Reaction Time
• Receptors, Nicotinic (drug effects, metabolism)
• Seizures (chemically induced, prevention & control)