Synthesis and X-ray crystal structure of 2-acetyl-9-azabicyclo[4.2.1]nonan-3-one. A conformationally locked s-cis analogue of anatoxin-a

Abstract

2- nonan-3-one 2 ('hydroxyanatoxin-a'), which represents a conformationally locked variant of the s-cisconformer of the potent cholinergic agonist anatoxin-a, is synthesised and characterised; this molecule lacks both nicotinic and muscarinic potency.

Neuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discovery

“…329 However, this molecule has a rotatable bond between the two putative pharmacophoric elements, and it remains uncertain which orientation of the acetyl side chain is the bioactive one. [332][333][334] The conformationally constrained analogue 83 of the s-trans conformation was synthesized by Hernandez and Rapoport to explore this issue. 332 Recent binding studies on this compound, reported here for the first time, 335 indicate that the K i value for displacement of [ 3 H]Cyt from rat brain membranes is 4.6 ( 1.1 nM (n ) 3), which is ca.…”

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

“…An alternative s-cis variant of anatoxin-a was designed within our groups in order to provide a mechanism for conformational constraint with a minimal structural disturbance [ 69 ]. Hydroxyanatoxin-a 18 uses the keto-enol tautomer of a 1,3-diketone (and the associated intramolecular hydrogen bond) as a conformational lock, and this system was shown (by X-ray crystallography and NMR) to exist as a “symmetrical” enol form i.e.…”