Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.
The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).
Tecle
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H
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106-1047, USA.
Barrett
S D
SD
Lauffer
D J
DJ
Augelli-Szafran
C
C
Brann
M R
MR
Callahan
M J
MJ
Caprathe
B W
BW
Davis
R E
RE
Doyle
P D
PD
Eubanks
D
D
Lipiniski
W
W
Mirzadegan
T
T
Moos
W H
WH
Moreland
D W
DW
Nelson
C B
CB
Pavia
M R
MR
Raby
C
C
Schwarz
R D
RD
Spencer
C J
CJ
Thomas
A J
AJ
Jaen
J C
JC
D016475:3T3 Cells; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D010091:Oximes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
D000067956:Adenylyl Cyclase Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D018721:Muscarinic Agonists; D010091:Oximes; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C096405:PD 142505-0028