Using physical chemistry to differentiate nicotinic from cholinergic agonists at the nicotinic acetylcholine receptor.
The binding of three distinct agonists-acetylcholine (ACh), nicotine, and epibatidine-to the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cation-pi interaction with Trp alpha149, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cation-pi interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp alpha149 suggests that a novel aromatic C-H...O=C hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information.
Cashin
Amanda L
AL
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA.
Petersson
E James
EJ
Lester
Henry A
HA
Dougherty
Dennis A
DA
D000109:Acetylcholine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018679:Cholinergic Agonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D009538:Nicotine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D055672:Static Electricity; D013499:Surface Properties; D013912:Threonine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018679:Cholinergic Agonists; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C011285:hydroxythreonine; D013912:Threonine; D009538:Nicotine; D014364:Tryptophan; C082748:epibatidine; D000109:Acetylcholine