Design, synthesis, and biological evaluation of substituted benzoate analogues of the selective nicotinic acetylcholine receptor antagonist, methyllycaconitine
Doisy X., Blagbrough IS., Wonnacott S., Potter BVL.
The norditerpenoid alkaloid methyllycaconitine (MLA) acts as a competitive antagonist on the nicotinic acetylcholine receptor (nAChR) with a high preference for the neuronal α-bungarotoxin (αBgt)-sensitive nAChR over the muscle nAChR in mammals. MLA is thus a useful pharmacological tool. Furthermore, its efficient binding to insect nAChR indicates a high insecticidal potency. Within the complex hexacyclic structure of MLA, we envisaged a potential simple pharmacophore. This led to the design and synthesis of acyclic and monocyclic analogues of MLA. The biological activity of these derivatives at both neuronal nicotinic and muscarinic AChR was evaluated. Some of these structurally simple compounds, despite displaying a modest affinity for the nAChR, showed good specificity. We were able to show the importance of the 2-(methylsuccinimido)benzoate ester moiety and the E-ring of MLA. None of the analogues tested displayed any affinity for [ 3 H]nicotine binding sites in brain membranes, indicating that α7-selectivity is already inherent in these simple structures. If higher affinities are to be obtained, however, there is a clear need for more structural information in the design of second generation simple analogues of MLA.