Agonist Efficiency Estimated from Concentration Response Curve

Concentration-response curves (CRCs) are characterized by a midpoint (EC50) and high-concentration asymptote (POmax) that relate to the agonist's affinity efficacy. Recently, third agonist attribute, efficiency, was defined as fraction of ligand binding energy is applied conformational change activates receptor. We show efficiency can be calculated from EC50 POmax estimate its value for 17 agonists nicotinic acetylcholine receptor (AChR). Adult skeletal muscle AChRs were expressed in HEK cells CRCs compiled single-channel currents POmax. There two populations having an 52±2% (n=11) or 41±3% (n=6) (mean±s.d). Agonists with smaller head-group volume (70±9 A3) have higher than those larger (102±18 A3). Examples high-efficiency/small-volume group include quaternary amines (ACh, carbamylcholine, tetramethyammonium others) well secondary (nornicotine, anabaesine DMPP). Low-efficiency/large-volume smoking-cessation drugs (varenicline cytosine), cations (tetraethlyammonium tetramethylphosphonium) (epibatidine, anatoxin). αY190A only one 22 site mutations affect ACh, switching it higher- lower-efficiency population. If known, estimated receptor's constitutive level activity any CRC.