Structure-activity relationships of methoctramine-related polyamines as muscarinic antagonist: effect of replacing the inner polymethylene chain with cyclic moieties

Bioorg Med Chem. 2007 Mar 15;15(6):2312-21. doi: 10.1016/j.bmc.2007.01.022. Epub 2007 Jan 19.

Abstract

The aim of the present paper was to investigate the role of the octamethylene spacer of methoctramine (1) on the biological profile. Thus, this spacer was incorporated into a dianiline or dipiperidine moiety to determine whether flexibility and the basicity of the inner nitrogen atoms are important determinants of potency with respect to muscarinic receptors. The most potent compound was 4, which displayed, in the functional assays, a comparable potency at muscarinic M(2) receptors with respect to 1, and, in the binding assays, a loss of potency and selectivity toward muscarinic M(1) and M(3) receptor subtypes. Both compounds were endowed with antinociceptive activity. Furthermore, in microdialysis tests in rat parietal cortex, they enhanced acetylcholine release, most likely by antagonizing presynaptic muscarinic receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Animals
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • CHO Cells / drug effects
  • Cerebral Cortex / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Cricetinae
  • Cricetulus
  • Diamines / chemistry*
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Guinea Pigs
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Humans
  • Ileum / drug effects
  • Ileum / metabolism
  • Male
  • Mice
  • Molecular Structure
  • Muscarinic Antagonists / chemical synthesis
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / pharmacology*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Parietal Lobe / drug effects
  • Photoaffinity Labels
  • Polyamines / chemical synthesis
  • Polyamines / chemistry
  • Polyamines / pharmacology*
  • Rabbits
  • Radioligand Assay
  • Rats
  • Receptors, Muscarinic / classification
  • Receptors, Muscarinic / drug effects
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / metabolism

Substances

  • Cholinesterase Inhibitors
  • Diamines
  • Muscarinic Antagonists
  • Photoaffinity Labels
  • Polyamines
  • Receptors, Muscarinic
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Acetylcholine
  • methoctramine