Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties.
This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.
Bridges
Thomas M
TM
Department of Pharmacology, Vanderbilt University Medical Center, 802 Robinson Research Building, Nashville, TN 37232, USA.
Brady
Ashley E
AE
Kennedy
J Phillip
JP
Daniels
R Nathan
RN
Miller
Nicole R
NR
Kim
Kwango
K
Breininger
Micah L
ML
Gentry
Patrick R
PR
Brogan
John T
JT
Jones
Carrie K
CK
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D000109:Acetylcholine / Q000737:chemistry; D000494:Allosteric Regulation; D000495:Allosteric Site; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry*; D043643:Receptor, Muscarinic M1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
C532626:1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one; D001562:Benzimidazoles; D008024:Ligands; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D000109:Acetylcholine