Solution structure and dynamics of cyclic and acyclic cholinergic agonists

Area of Science:

• Medicinal Chemistry
• Biophysical Chemistry
• Structural Biology

Background:

• Nicotinic cholinergic agonists are crucial drug targets.
• Understanding structure-activity relationships is key to drug design.
• Previous studies indicated cyclic analogs are more potent than acyclic ones.

Purpose of the Study:

• To investigate the structural and dynamic properties of novel nicotinic cholinergic agonists.
• To elucidate the molecular basis for the increased potency of cyclic agonists.
• To characterize the conformational preferences and energetics of amide bond isomerization.

Main Methods:

• Synthesis of cyclic and acyclic nicotinic cholinergic agonists.
• Nuclear Magnetic Resonance (NMR) spectroscopy (1D and 2D) for structural analysis.
• Variable temperature NMR to study amide bond isomerization energetics.

Main Results:

• Identified two distinct stable conformers differing in amide bond orientation for both cyclic and acyclic compounds.
• Cyclic compounds exhibited equal energy conformers, while acyclic compounds (N,N,N,N'-tetramethyl-N'-acetylethylene-diamine iodide - TED) showed energetically unequal conformations.
• The more populated TED conformer is stabilized by electrostatic attraction between the carbonyl oxygen and quaternary amine nitrogen.

Conclusions:

• Conformational differences and amide bond isomerization kinetics of TED derivatives may hold biological significance.
• The study provides insights into how molecular flexibility and electrostatic interactions affect agonist potency.
• Structural characterization via NMR advances the understanding of nicotinic receptor ligand interactions.