ACh transmission modulators

Nicotine

• agonist

• binds to neuronal nAChR, activating it

  • releases dopamine

• similar structure to ACh

chantix (varenicline)

• partial agonist: competitive modulator

  • binds more tightly to nAChR than nicotine but does not cause receptor to open as much

• partial mimicry of ACh structure: ring system instead

Conotoxin (snail venom)

• antagonist, binds to muscle nAChR

• prevents channel from open (cys loop pushed out)

  • no muscle activation

• structure: surface is rigid and structured

galantamine

• noncompetitive inhibitor, binds to allosteric sites on nAChRs in prescence/absence of ACh

  • decreases activation of the nAChR

• competitive reversible inhibitor of acetylcholinesterase (AChE)

  • binding prevents hydrolysis of ACh in neurons

  • slows cognitive decline in AD patients

hemicholinium

• mimics Choline, binds in cleft of choline transporter but too large to pass through

  • slows ACh synthesis

  • can offset ACh accumulation by VX

VX Gas

• irreversibly inhibits AChE: its phosphonate not hydrolyzed; highly reactive

  • active site serine of AChE attacks phosphorus instead of breaking down ACh using the Ser-His-Glu triad

Botox

• heavy chain binds to synaptotagmin

  • gets imported with recycled empty vesicles

• light chain released into cytosol

  • cleaves SNARE proteins

  • ACh release into synaptic cleft inhibited

  • no muscle contraction

epibatidine

• agonist of ACh

• very high binding affinity, very potent

• blocks pain receptors without being an opioid but very toxic