Synthesis and SAR of bulky 1-azabicyclo[2.2.1]-3-one oximes as muscarinic receptor subtype selective agonists.
The synthesis of a series of potent and efficacious 1-azabicyclo[2.2.1]heptan-3-one oxime muscarinic agonists is described. The oximes have extended appendages designed to span the cavity defined by the seven transmembrane helices of the muscarinic receptor. Some members of the series are selective for receptors of the m1 subtype. One such oxime, 31, shows affinity and functional selectivity for m1 over m2, m3, and m4 muscarinic receptor types.
Tecle
H
H
Parke-Davis Pharm. Res. Div., Warner-Lambert Co. Ann Arbor, MI 48105.
Lauffer
D J
DJ
Mirzadegan
T
T
Moos
W H
WH
Moreland
D W
DW
Pavia
M R
MR
Schwarz
R D
RD
Davis
R E
RE
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004148:Dioxolanes / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D004148:Dioxolanes; D007295:Inositol Phosphates; D008024:Ligands; D010091:Oximes; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D005576:Colforsin; C024310:2-methyldioxolane; D011813:Quinuclidinyl Benzilate; D000242:Cyclic AMP