RT Journal Article SR Electronic T1 Discovery of an Ectopic Activation Site on the M1Muscarinic Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1297 OP 1302 DO 10.1124/mol.61.6.1297 VO 61 IS 6 A1 Spalding, Tracy A. A1 Trotter, Carol A1 Skjærbæk, Niels A1 Messier, Terri L. A1 Currier, Erika A. A1 Burstein, Ethan S. A1 Li, Donghui A1 Hacksell, Uli A1 Brann, Mark R. YR 2002 UL http://molpharm.aspetjournals.org/content/61/6/1297.abstract AB 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.