Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.
This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.
Lewis
L Michelle
LM
Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
Sheffler
Douglas
D
Williams
Richard
R
Bridges
Thomas M
TM
Kennedy
J Phillip
JP
Brogan
J T
JT
Mulder
Matthew J
MJ
Williams
Lyndsey
L
Nalywajko
Natalia T
NT
Niswender
Colleen M
CM
Weaver
Charles D
CD
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic