Conformational studies on (+)-anatoxin-a and derivatives

Abstract

Anatoxin-a (AnTX) is a highly potent agonist acting at the nicotinic acetylcholine receptor (nAChR) and represents a valuable tool in the study of this receptor. Molecular mechanics, semi-empirical and ab initio molecular orbital energy minimization procedures were conducted to investigate the conformation of AnTX. For each minimization procedure, the s-trans enone isomer of protonated AnTX was the energetically favoured conformer due to intramolecular electrostatic interactions. Our studies are discussed in the light of previous experimental observations and conformational studies, in addition to their importance in the development of future pharmacophore models for nAChR agonist binding.

The Chemistry and Pharmacology of Anatoxin-a and Related Homotropanes with respect to Nicotinic Acetylcholine Receptors

“…Later calculations using the protonated and, given the pk A of anatoxin-a, the biologically more relevant form of anatoxina concluded that not only was the energy difference between s-cis and s-trans larger (9.4 kJ mol −1 ) but that it also favoured the s-trans conformer i.e. s-trans was more stable [ 64 ]. The message to take from this is that no truly definitive conclusions can be drawn from either set of calculations.…”

A Computational Study of Nicotine Conformations in the Gas Phase and in Water

“…In addition, they were conducted in the gas phase, ignoring possible effects arising from interactions with water. Recently, more modern computational techniques have been used to study the conformations of other nAChR ligands: ACh, epibatidene, and anatoxin-a, and it thus seemed appropriate to perform a comparable study on nicotine.…”

Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (−)-hosieine-A

“…We also considered data on the conformation of the ligand itself. Solution NMR and force-field calculations suggest that cis-and trans-chair conformations of this alkaloid are similar in energetic terms, with an approximate ratio of 3:1, and the acetyl side chain is relatively free to rotate (Thompson et al, 1992). Single-crystal X-ray diffraction analyses of an acetyl derivative (Huber, 1972) and (+)-anatoxin-a itself (Koskinen & Rapoport, 1985) show the trans-chair conformation.…”