title: Synthesis and in vitro characterization of novel amino terminally modified oxotremorine derivatives for brain muscarinic receptors.
abstract: 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.
authors.affiliation: Neuroscience Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: D S
authors.initials: DS
authors.lastname: Garvey
authors.forename: J T
authors.initials: JT
authors.lastname: Wasicak
authors.forename: J Y
authors.initials: JY
authors.lastname: Chung
authors.forename: Y K
authors.initials: YK
authors.lastname: Shue
authors.forename: G M
authors.initials: GM
authors.lastname: Carrera
authors.forename: P D
authors.initials: PD
authors.lastname: May
authors.forename: M M
authors.initials: MM
authors.lastname: McKinney
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: E
authors.initials: E
authors.lastname: Cadman
authors.forename: L
authors.initials: L
authors.lastname: Vella-Rountree
mesh_terms: 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
chemical_list: D011976:Receptors, Muscarinic; D010890:Pirenzepine; D010095:Oxotremorine