Discovery of an ectopic activation site on the M(1) muscarinic receptor.
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 M(1) 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.
Spalding
Tracy A
TA
ACADIA Pharmaceuticals, Inc., San Diego, California 92121, USA. tspalding@acadia-pharm.com
Trotter
Carol
C
Skjaerbaek
Niels
N
Messier
Terri L
TL
Currier
Erika A
EA
Burstein
Ethan S
ES
Li
Donghui
D
Hacksell
Uli
U
Brann
Mark R
MR
D016475:3T3 Cells; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*
C456520:4-n-butyl-1-(4-(2-methylphenyl)-4-oxo-1-butyl)-piperidine hydrogen chloride; D018721:Muscarinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D000109:Acetylcholine