TY - JOUR T1 - Discovery of an Ectopic Activation Site on the M<sub>1</sub>Muscarinic Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1297 LP - 1302 DO - 10.1124/mol.61.6.1297 VL - 61 IS - 6 AU - Tracy A. Spalding AU - Carol Trotter AU - Niels Skjærbæk AU - Terri L. Messier AU - Erika A. Currier AU - Ethan S. Burstein AU - Donghui Li AU - Uli Hacksell AU - Mark R. Brann Y1 - 2002/06/01 UR - http://molpharm.aspetjournals.org/content/61/6/1297.abstract N2 - Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M1 muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this ligand activates the receptor through a region that is not conserved among receptor subtypes, explaining its unprecedented selectivity. This region of the receptor is distinct from the conserved region that is recognized by traditional ligands. The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity. ER -