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 [ 125I]iodo-MLA binding at rat brain α7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b–f were evaluated for inhibition of binding to rat brain α,β nAChR using [ 3H]epibatidine. At the α7 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 α,β 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 α7 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 β-amyloid 1–42, these new analogs which have high α7 nAChR affinity and good selectivity relative to α,β nAChRs will be useful biological tools for studying the effects of α7 nAChR antagonist and neuroprotection.