Torsional rotation in the ACh molecule can occur around bonds τ₁, τ₂ and τ₃ (Fig. 11-1). Since the methyl groups are disposed symmetrically around τ₃ and constraints may be placed on τ₁ by the planar acetoxy group, the most important torsion angle determining ACh conformation in solution is τ₂. A view from the β-methylene carbon of the molecule (Fig. 11-1) shows the lowest energy configurations around τ₂. Nuclear magnetic resonance (NMR) studies indicate that the gauche conformation is predominant in solution [5,6]. Studies of the activities of rigid analogs of ACh suggest that the trans conformation may be the active conformation at muscarinic receptors [7], while results of NMR studies show that the acetoxy and quaternary nitrogens in the bound state of ACh are too close together for this conformation to exist when ACh is bound to the nicotinic receptor [6]. Hence, the bound conformations of this flexible molecule appear to differ substantially with receptor subtype. This finding should not emerge as a great surprise since it has been known for years that the structural modifications that enhance or diminish activity on muscarinic receptors are very different from those modifications that influence activity on nicotinic receptors [8].

Figure 11-1

Structure of acetylcholine. A: The three torsion angles τ₁, τ₂ and τ₃. B: Newman projection of the gauche conformation. C: Newman projection of the trans conformation. The molecule is viewed in the plane of the paper from the left (more...)