Synthesis and in vitro characterization of novel amino terminally modified oxotremorine derivatives for brain muscarinic receptors.
A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors. One analogue, 3-(2-oxo-1-pyrrolidinyl)-1-[2(R)-pyrrolidinyl]-1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1. The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue. All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different. While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.
Garvey
D S
DS
Neuroscience Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Wasicak
J T
JT
Chung
J Y
JY
Shue
Y K
YK
Carrera
G M
GM
May
P D
PD
McKinney
M M
MM
Anderson
D
D
Cadman
E
E
Vella-Rountree
L
L
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010890:Pirenzepine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
D011976:Receptors, Muscarinic; D010890:Pirenzepine; D010095:Oxotremorine