Synthesis and biological characterization of a series of novel diaryl amide M₁ antagonists.
Utilizing a combination of high-throughput and multi-step synthesis, SAR in a novel series of M(1) acetylcholine receptor antagonists was rapidly established. The efforts led to the discovery the highly potent M(1) antagonists 6 (VU0431263), and 8f (VU0433670). Functional Schild analysis and radioligand displacement experiments demonstrated the competitive, orthosteric binding of these compounds; human selectivity data are presented.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. mike.poslusney@vanderbilt.edu
Michael S
MS
Poslusney
Christian
C
Sevel
Thomas J
TJ
Utley
Thomas M
TM
Bridges
Ryan D
RD
Morrison
Nathan R
NR
Kett
Douglas J
DJ
Sheffler
Colleen M
CM
Niswender
J S
JS
Daniels
P J
PJ
Conn
Craig W
CW
Lindsley
Michael R
MR
Wood
D000109:Acetylcholine / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D010879:Piperazines; D043643:Receptor, Muscarinic M1; D013267:Stilbenes; C578848:VU0431263; C578849:VU0433670; D000109:Acetylcholine