Synthesis and in vitro characterization of novel amino terminally modified oxotremorine derivatives for brain muscarinic receptors

J Med Chem. 1992 May 1;35(9):1550-7. doi: 10.1021/jm00087a008.


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.

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism*
  • Corpus Striatum / metabolism*
  • Magnetic Resonance Spectroscopy
  • Male
  • Oxotremorine / analogs & derivatives*
  • Oxotremorine / chemical synthesis
  • Oxotremorine / metabolism
  • Oxotremorine / pharmacology
  • Pirenzepine / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism


  • Receptors, Muscarinic
  • Pirenzepine
  • Oxotremorine